We have developed a partially purified, polyvalent melanoma vaccine from surface material shed into culture medium by a pool of selected melanoma cells. The vaccine contains a broad spectrum of melanoma antigens to circumvent the antigenic heterogeneity of melanoma and to obviate the need to identify individual antigens that mediate tumor-protective immunity. Vaccine treatment augments antimelanoma humoral and/or cellular immunity in over 50% of patients and can increase immunity to a patient's own melanoma. Vaccine-induced antibodies are directed at one or more surface antigens with molecular masses of 210, 150, 110, 75, or 38 kDa. The 210- and 110-kDa antigens are melanoma associated, as they were expressed by four of five human melanoma cell lines, but by only two of 12 control cell lines, and are unrelated to previously described melanoma antigens. The disease-free (DF) and overall survival (OS) of vaccine-treated patients with surgically resected stage II (regional) disease is 50% longer than that of historical controls. Survival is particularly prolonged in patients who develop an immune response. Median DF survival is 4.7 years longer and OS 3.7 years longer in patients with a strong, as opposed to no, cellular immune response to vaccine treatment (p = < 0.02). Similarly, median DF survival of patients with vaccine-induced melanoma antibodies is significantly longer than that of nonresponders (65 months vs. 17 months, respectively), as is overall survival (p = 0.01). These differences in outcome are unrelated to disease severity or to the overall immunological competence of the patients, suggesting they result from vaccine treatment. Thus melanoma vaccine treatment is safe, capable of stimulating antimelanoma immunity in many patients, and appears to be clinically effective in delaying the progression of this cancer in some individuals.