Six patients with intradermal metastases of malignant melanoma were treated with intralesional bacile Calmette-Guérin (BCG). Four patients showed a good response with regression of injected, and in some cases, uninjected lesions, whereas two developed metastatic viscereal disease and died. Three of the six patients had complete regression of all lesions, and one exhibited complete regression of untreated lesions. All remain free of disease. The fourth patient had complete regression of injected and of some untreated lesions, but developed widespread dissemination and died. Preliminary experiments suggest the presence of a blocking factor in his sera which abrogates the lymphocyte stimulation in response to melanoma antigens. Three of four responders (i.e. those patients in whom treated lesions decreased in size by more than 50% for more than 1 month) showed a dramatic increase in lymphocyte stimulation to melanoma antigens. All responders (four out of four) had a marked increase to phytohemagglutinin (PHA), whereas non responders had no increase in lymphocyte stimulation either to melanoma antigens or PHA. Two of four responders showed inhibition of leukocyte migration to melanoma antigens before BCG, and two of four responders were positive after BCG. Of the nonresponders, one was positive and one negative before BCG; this remained the same after. There was a marked increase in active rosette forming cells in all responders and in one of the two nonresponders. Histopathologic studies at 3 hours, 6 hours, 24 hours, 14 days, and 4 weeks after BCG showed a definite sequence of events occurred, progressing from 1) inflammatory cell response at the periphery of the lesion, disruption of melanogenesis, extensive dumping of pigment from melanoma cells, proceeding to actual cell death at 24 hours, to 2) macrophages containing melanin and granulomas replacing tumor by 2 weeks. These studies suggest that BCG activates both specific and nonspecific immune responses. Thus, in vitro parameters of cellular immunity, including migration inhibitory factor production and inhibition of leukocyte migration, are affected by intralesional BCG, and some, particularly the lymphocyte stimulation and rosette test, seem to correlate with the clinical response of the patients.