Clinical trials of melanoma vaccines have yielded inconclusive data on whether a positive melanoma-specific immune response predicts treatment benefit. The objective of this study was to evaluate the effect of different melanoma vaccine strategies and the association between immunologic response and survival. The authors conducted a systematic review and meta-analysis of phase II and III clinical trials of melanoma vaccine. Outcomes assessed included overall disease control, overall survival, and impact on immune response. For binary variables, proportions were reported for one-arm studies and risk ratios for controlled studies. For survival data, medians were reported for one-arm studies and hazard ratios for controlled studies. The existence and extent of heterogeneity between trials was evaluated using Cochran's Q statistic. A two-sided P value of less than 0.05 for meta-analysis results was considered statistically significant. Of 56 studies reporting data on 4375 patients, overall disease control was seen in 25.3% [95% confidence interval (CI): 20.7-30.5%] of patients. Subgroup analysis revealed that overall disease control for peptide vaccines plus interleukin-2 (IL-2) was improved compared with interleukin-2 alone (pooled risk ratio: 2.79, 95% CI: 1.62-4.80). Overall survival varied among six studies comparing vaccine with other treatments. Subgroup analysis revealed that tumor-specific immune response was associated with prolonged overall survival compared with the lack of response (pooled hazard ratio: 2.15, 95% CI: 1.88-2.44). Severe toxicity associated with vaccine treatment was uncommon. Overall, a melanoma-specific immune response predicted longer overall survival, although no evidence was found that vaccine therapy provides better overall disease control or overall survival compared with other treatments.