Interleukin-2 (IL-2), initially used in 1986, can induce clinical regression-complete responses (CR) and partial responses (PR) of metastatic malignant melanoma. IL-2 has been used alone or in combination, and in different dosage schedules, as an immunotherapeutic agent for melanoma treatment. This meta-analysis aimed to document and evaluate the spectrum of reported clinical response rates from the combined experience of almost 30 years of IL-2 clinical usage. Clinical trials using IL-2 for metastatic melanoma therapy that reported: dosage, combinations, study details, definitions and clinical CR, PR, and overall response (OR) rates were included. A meta-analysis was conducted using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. In total, 34 studies met inclusion criteria, with 41 separate treatment arms. For all IL-2 treatment modalities collectively, the CR rate was 4.0% [95% confidence interval (CI), 2.8-5.3], PR 12.5% (95% CI, 10.1-15.0), and OR 19.7% (95% CI, 15.9-23.5). CR pre-1994 was 2.7% versus 6.1% post-1994. High and intermediate-IL-2 dosage showed no CR difference, while low-dose IL-2 showed a nonstatistical trend toward an increased CR rate. The highest CR rate resulted from IL-2 combined with vaccine at 5.0%. The meta-analysis showed that IL-2 immunotherapy for advanced metastatic melanoma delivered a CR rate of 4% (range, 0-23%) across nearly 30 years of clinical studies, with gradual improvement over time. The significance is that, contrary to popular belief, the data demonstrated that CR rates were similar for intermediate versus high-IL-2 dosing.