diff --git a/pkg/store/prometheus.go b/pkg/store/prometheus.go
index 990d0a2bbb..cbcc8e0189 100644
--- a/pkg/store/prometheus.go
+++ b/pkg/store/prometheus.go
@@ -6,6 +6,7 @@ import (
 	"encoding/json"
 	"fmt"
 	"io"
+	"math"
 	"net/http"
 	"net/url"
 	"path"
@@ -155,19 +156,16 @@ func (p *PrometheusStore) Series(r *storepb.SeriesRequest, s storepb.Store_Serie
 			continue
 		}
 
-		// We generally expect all samples of the requested range to be traversed
-		// so we just encode all samples into one big chunk regardless of size.
-		enc, cb, err := p.encodeChunk(e.Samples)
+		// XOR encoding supports a max size of 2^16 - 1 samples, so we need
+		// to chunk all samples into groups of no more than 2^16 - 1
+		aggregatedChunks, err := p.chunkSamples(e, math.MaxUint16)
 		if err != nil {
-			return status.Error(codes.Unknown, err.Error())
+			return err
 		}
+
 		resp := storepb.NewSeriesResponse(&storepb.Series{
 			Labels: lset,
-			Chunks: []storepb.AggrChunk{{
-				MinTime: int64(e.Samples[0].Timestamp),
-				MaxTime: int64(e.Samples[len(e.Samples)-1].Timestamp),
-				Raw:     &storepb.Chunk{Type: enc, Data: cb},
-			}},
+			Chunks: aggregatedChunks,
 		})
 		if err := s.Send(resp); err != nil {
 			return err
@@ -176,6 +174,33 @@ func (p *PrometheusStore) Series(r *storepb.SeriesRequest, s storepb.Store_Serie
 	return nil
 }
 
+func(p *PrometheusStore) chunkSamples(series prompb.TimeSeries, samplesPerChunk int) ([]storepb.AggrChunk, error) {
+	var aggregatedChunks []storepb.AggrChunk
+	samples := series.Samples
+
+	for len(samples) > 0 {
+		chunkSize := len(samples)
+		if chunkSize > samplesPerChunk  {
+			chunkSize = samplesPerChunk
+		}
+
+		enc, cb, err := p.encodeChunk(samples[:chunkSize])
+		if err != nil {
+			return nil, status.Error(codes.Unknown, err.Error())
+		}
+
+		aggregatedChunks = append(aggregatedChunks, storepb.AggrChunk{
+			MinTime: int64(samples[0].Timestamp),
+			MaxTime: int64(samples[chunkSize-1].Timestamp),
+			Raw:     &storepb.Chunk{Type: enc, Data: cb},
+		})
+
+		samples = samples[chunkSize:]
+	}
+
+	return aggregatedChunks, nil
+}
+
 func (p *PrometheusStore) promSeries(ctx context.Context, q prompb.Query) (*prompb.ReadResponse, error) {
 	span, ctx := tracing.StartSpan(ctx, "query_prometheus")
 	defer span.Finish()
diff --git a/pkg/store/prometheus_test.go b/pkg/store/prometheus_test.go
index 2bfca8876a..567d6a5fe1 100644
--- a/pkg/store/prometheus_test.go
+++ b/pkg/store/prometheus_test.go
@@ -3,6 +3,7 @@ package store
 import (
 	"context"
 	"fmt"
+	"math"
 	"net/url"
 	"testing"
 	"time"
@@ -272,3 +273,71 @@ func TestPrometheusStore_Info(t *testing.T) {
 	testutil.Equals(t, int64(123), resp.MinTime)
 	testutil.Equals(t, int64(456), resp.MaxTime)
 }
+
+// Regression test for https://github.com/improbable-eng/thanos/issues/396.
+func TestPrometheusStore_Series_SplitSamplesIntoChunksWithMaxSizeOfUint16_e2e(t *testing.T) {
+	defer leaktest.CheckTimeout(t, 10*time.Second)()
+
+	p, err := testutil.NewPrometheus()
+	testutil.Ok(t, err)
+
+	baseT := timestamp.FromTime(time.Now().AddDate(0, 0, -2)) / 1000 * 1000
+
+	a := p.Appender()
+
+	offset := int64(2*math.MaxUint16 + 5)
+	for i := int64(0); i < offset; i++ {
+		_, err = a.Add(labels.FromStrings("a", "b"), baseT+i, 1)
+		testutil.Ok(t, err)
+	}
+
+	testutil.Ok(t, a.Commit())
+
+	ctx, cancel := context.WithCancel(context.Background())
+	defer cancel()
+
+	testutil.Ok(t, p.Start())
+	defer func() { testutil.Ok(t, p.Stop()) }()
+
+	u, err := url.Parse(fmt.Sprintf("http://%s", p.Addr()))
+	testutil.Ok(t, err)
+
+	proxy, err := NewPrometheusStore(nil, nil, u,
+		func() labels.Labels {
+			return labels.FromStrings("region", "eu-west")
+		}, nil)
+	testutil.Ok(t, err)
+	srv := newStoreSeriesServer(ctx)
+
+	testutil.Ok(t, proxy.Series(&storepb.SeriesRequest{
+		MinTime: baseT,
+		MaxTime: baseT + offset,
+		Matchers: []storepb.LabelMatcher{
+			{Type: storepb.LabelMatcher_EQ, Name: "a", Value: "b"},
+			{Type: storepb.LabelMatcher_EQ, Name: "region", Value: "eu-west"},
+		},
+	}, srv))
+
+	testutil.Equals(t, 1, len(srv.SeriesSet))
+
+	firstSeries := srv.SeriesSet[0]
+
+	testutil.Equals(t, []storepb.Label{
+		{Name: "a", Value: "b"},
+		{Name: "region", Value: "eu-west"},
+	}, firstSeries.Labels)
+
+	testutil.Equals(t, 3, len(firstSeries.Chunks))
+
+	chunk, err := chunkenc.FromData(chunkenc.EncXOR, firstSeries.Chunks[0].Raw.Data)
+	testutil.Ok(t, err)
+	testutil.Equals(t, math.MaxUint16, chunk.NumSamples())
+
+	chunk, err = chunkenc.FromData(chunkenc.EncXOR, firstSeries.Chunks[1].Raw.Data)
+	testutil.Ok(t, err)
+	testutil.Equals(t, math.MaxUint16, chunk.NumSamples())
+
+	chunk, err = chunkenc.FromData(chunkenc.EncXOR, firstSeries.Chunks[2].Raw.Data)
+	testutil.Ok(t, err)
+	testutil.Equals(t, 5, chunk.NumSamples())
+}