Evidence for the increased immunogenicity of mastocytoma cells (P815) treated with 8-methoxypsoralen (8-MOP) and long-wavelength ultraviolet radiation (UVA) is presented. A highly tumorigenic clone (P1) became much less tumorigenic (tum-) after repetitive phototreatments with 8-MOP (16 ng/mL) and UVA (1 J/cm2). The yield of tum- clones was proportional to the number of phototreatments. In a pilot study in which P1 cells were treated with three successive rounds of 8-MOP/UVA, one clone out of 73 was tum-. In a second series of experiments, the P1 cells were treated 10 times and 4 out of 100 clones were much less tumorigenic. When some of the tum- clones were administered intraperitoneally to DBA/2 mice, significant protection against challenge with the original P1 clone was observed. In addition, the transfer of immune cells from tum(-)-treated mice allowed the transfer of resistance to other tum- clones to immunosuppressed mice (650 rad). These results are consistent with earlier literature showing the potent mutagen, N-methyl-N'-nitrosoguanidine, led to mutations in P1 that altered the expression of new surface antigens, which stimulated the murine immune system such that there was also cross recognition of shared antigens on untreated P1 cells used to challenge the immunized mice. The increased immunogenicity that resulted from the less mutagenic 8-MOP/UVA treatment may arise by a similar mechanism and may be responsible in part for the efficacy of 8-MOP/UVA photochemotherapy for the treatment of cutaneous T cell lymphoma.