Amberlite XAD 4 resin hemoperfusion was studied in the treatment of massive digitoxin overdosage. In vitro experiments using 4 hour resin hemoperfusion showed that digitoxin is removed 100 percent from an isotonic saline reservoir, 83 +/- 14 percent from plasma, and 42 +/- 7 percent from whole blood. In dogs, serum level reduction is fast: 50 +/- 12 percent in 15 minutes, 71 +/- 6 percent in 180 minutes; mean plasma clearance is 24 +/- 6.5 ml/min for a 150 ml/min plasma flow rate. Eleven patients with massive digitoxin overdosage recovered with resin hemoperfusion. Serum level reduction was 32 +/- 14 percent with a 325 g resin column, 59 +/- 6 percent with two 325 g resin columns in series as compared with a 4.5 +/- 1.7 percent reduction without perfusion. Hemoperfusion increased the rate of spontaneous removal of digitoxin 8.6 +/- 3.3 times with a 325 g resin column, and 14 +/- 7.4 times with two 325 g resin columns.