Canine transmissible venereal tumors were studied for response to intralesional Bacillus Calmette-Guérin (BCG) therapy. Six pairs of littermates, identical for the major histocompatibility complex, were evaluated. One member of each pair received intralesional BCG to one of two growing tumors. Lesions of control animals received 0.9% NaCl solution. Both injected and noninjected lesions of BCG-treated animals underwent regression within 63 days, as compared to an extended period of tumor growth (beyond 100 days) for controls (p less than 0.05). Serial in vitro assays during therapy included; (a) mixed lymphocyte-tumor culture, (b) phytohemagglutinin stimulation, and (c) assessment of lymphocyte surface markers. Lymphocytes from BCG-treated dogs were significantly more responsive to tumor cells in mixed lymphocyte-tumor culture assay than were those from controls (p less than 0.05). Maximal responses occurred during tumor regression. T- and B-lymphocyte levels as assayed by rosette formation and surface marker immunoglobulins were not influenced by BCG therapy. It was concluded that intralesional BCG therapy of canine venereal tumors was highly effective in causing regression of injected and noninjected lesions. This tumor model system may be useful for the evaluation of the effectiveness of new immunotherapeutic approaches on established neoplasms in large, randomly bred animals.