The growth and spontaneous resolution of syngeneic intraocular tumors were studied in DBA/2 mice. The P91 mutant clone of P815 mastocytoma (DBA/2 origin) expresses potent tumor-specific transplantation antigens (TSTA) that elicit vigorous immune responses in the syngeneic host. P91 tumors grew transiently and underwent spontaneous resolution following intracameral transplantation in DBA/2 hosts. The spontaneous rejection of the intraocular P91 tumors was a T-cell-dependent, radiosensitive immune process since these tumors grew progressively in T-cell-deficient nude mice and sublethally x-irradiated DBA/2 hosts. Intraocular P91 tumors induced vigorous cytotoxic T-lymphocyte (CTL), antibody, and delayed-type hypersensitivity (DTH) responses in immunocompetent DBA/2 hosts. The acquisition of DTH and CTL reactivity against the TSTA on the intraocular P91 tumors coincided with the onset of spontaneous rejection and suggested a pivotal role for cellular immune mechanisms in the destruction of the primary intraocular neoplasms. Moreover, histopathologic features attending tumor regression were compatible with the DTH reaction in the mouse. Tumor regression was associated with extensive vascular margination and emigration of neutrophils among viable tumor cells at the interface of the tumor mass and uveal components. Areas of previous tumor growth were replaced by a bed of granulation tissue accompanied by a mixed inflammatory infiltrate. Although immunocompetent hosts were able to rid their eyes of tumor, all of the eyes eventually became phthisical. The present findings are consistent with the hypothesis that cellular immune processes play a major role in the spontaneous rejection of intraocular tumors.