Intrarenal injection of 10 mg Ni3S2 elicits polycythemia in rats. This can be attributed either to direct stimulation or to erythropoietin-induced hyperplasia of erythropoietic elements of bone marrow. While studying the mechanism of this experimental model of polycythemia it was noted that: extirpation of the injected kidney after the development of the hematologic alterations abolished the polycythemia within 1 mo.; i.v., i.m. or intrahepatic treatment with Ni3S2 was ineffective in producing polycythemia; and there was a modest but statistically significant elevation of plasma erythropoietin levels in rats 2, 4 and 8 wk after injection of Ni3S2, at a time when the hematocrit values were increased. Ni3S2 apparently does not directly stimulate erythropoiesis in bone marrow but primarily affects the injected kidney, which in turn (by the continuous liberation of modest amounts of erythropoietin or some hitherto unknown substance) triggers the development of polycythemia.