To elucidate the initial steps of carcinogenesis by nickel subsulfide, the mechanisms of dissolution of .alpha.-Ni3S2 were studied by incubating .alpha.-Ni3S2 dust in water, rat serum and rat serum ultrafiltrate. The sediments that remained following incubation of .alpha.-Ni3S2 in the 3 media for 2 wk were examined by X-ray diffractometry. The rates of solubilization of 63Ni from .alpha.-63Ni3S2 during incubation in the 3 media were measured by liquid scintillation counting. These studies showed that solubilization of Ni (II) from .alpha.-Ni3S2 in rat serum requires the presence of O2 and involves 3 reactions: 2.alpha.-Ni3S2 + O2 + 2H2O .fwdarw. 4 .beta.-NiS + 2Ni[OH]2; .beta.-NiS + 2O2 .fwdarw. Ni2+ + SO42- and Ni2+ and Ni [OH]2 + serum ligands [albumin and amino acids] .fwdarw. soluble Ni (II)-complexes. The rate of solubilization of 63Ni from .alpha.-63Ni3S2 was initially more rapid in rat serum than in serum ultrafiltrate and more rapid than in water. After 2 days of incubation, the rates of dissolution of .alpha.-63Ni3S2 in the 3 media became progressively retarded, probably owing to deposition of insoluble surface coatings of .beta.-63NiS and 63Ni[OH]2 on the .alpha.-63Ni3S2 particles.