After 2 days of dosing, platelet counts progressively declined in dogs treated orally with 30 mg/kg/day of the antidepressant compound MDL 19,660 for 8 days. Accompanying the decrease in platelet counts was an increase in both large and vacuolated degenerating platelets. Upon cessation of dosing, the platelet counts returned to levels equal to or exceeding predosing levels within 4-7 days. Co-administration with aspirin, a known antiaggregating agent, had no protective effect on the drug-induced thrombocytopenia. In vitro testing of normal canine platelets in the presence of MDL 19,660 further revealed that spontaneous aggregation did not occur and that ADP-induced aggregation was inhibited. Drug-related platelet loss was also not prevented by the co-administration of prednisone, a steroid with immunosuppressive effects and inhibitory properties against reticuloendothelial cell phagocytosis of platelets. The results of the present investigation indicate that MDL 19,660 may produce in the dog a reversible thrombocytopenia in the form of vacuolar degeneration and subsequent destruction of the platelet by means other than aggregation or steroid-responsive mechanisms.