Temozolomide (TMZ) has received much attention, notably in the treatment of malignant glioma and malignant melanoma. The objective of this study was to compare the clinical efficacy and safety of TMZ alone and TMZ-based combination drug therapy in patients with melanoma. Using "temozolomide" as a keyword combined with "melanoma" and "randomized controlled trials" as Medical Subject Headings, the following electronic databases were searched: the Cochrane library, MEDLINE, EBSCO, EMBASE, Ovid, cNKI, and cBMDisc. The evaluating indicators were overall response rate (ORR), 1-year survival rate, and several of the most frequent adverse events. Five randomized controlled trials met our criteria and were included in the meta-analysis, with a total of 703 participants (309 patients received TMZ alone, and 394 patients received combined regimens). The meta-analysis showed that the ORR for TMZ-based drug therapy was higher than TMZ alone [relative risk (RR) = 1.44; 95% confidence interval (CI), 1.06-1.95], but the 1-year survival rate was not significantly different between the two groups (RR = 1.13; 95% CI, 0.92-1.40). These results suggested that the impact of these increased response rates was not translated into a survival benefit. Moreover, we found no difference in the incidence of adverse events analyzed. The currently available evidence showed that the TMZ-combination therapy may moderately improve the response rate, but there was no corresponding increased toxicity. Future large-scale, high-quality, placebo-controlled, double-blind trials are needed.