After intrarenal (i.r.1 administration of 5 mg of nickel subsulfide (alpha Ni3S2) to Fischer rats, blood hematocrit became increased within one week and reached 76 +/- 1 percent at eight weeks (p less than 0.001 versus mean hematocrit of 46 +/- 1 percent in control rats). The alpha Ni3S2-induced erythrocytosis was attended by intense stimulation of erythropoiesis, with reticulocytosis, increased 59Fe-uptake into erythrocytes and erythroid hyperplasia in bone marrow and spleen. The half-life of 51Cr-labeled erythrocytes from alpha Ni3S2-treated rats was prolonged, consistent with increased proportion of circulating juvenile erythrocytes. Histological examination of rat kidneys after i.r. injection of alpha Ni3S2 showed mild inflmmation at one and two weeks. Dense black particles of alpha Ni3S2 were visible in histological sections of rat kidneys for eight weeks. 5'-Nucleotidase activity in rat kidney microsomes was inhibited at one to seven days after i.r. injection of alpha Ni3S2. Erythrocytosis did not occur in rats after (a) i.r. implantation of semi-permeable cellulose tubules containing alpha Ni3S2, (b) repeated i.m. injections of alpha Ni3S2, or (c) intrahepatic injection of alpha Ni3S2 after partial hepatectomy. Erythrocytosis did not occur in male BALB/c mice or ground squirrels after i.r. injection of alpha Ni3S2.