&NA;The biological mechanisms of chemoimmunotherapy efficacyin vivohave not been fully clarified; furthermore, few data are available to predict its efficacy on the basis of clinical and immunological pretreatment factors. In this paper, pre‐ and post‐treatment serum levels of cytokines (interleukin [IL]‐6, IL‐10, IL‐12 and neopterin) and soluble IL‐2 receptors (sIL‐2R), as well as circulating levels of T‐cell and NK subpopulations, were analysed according to clinical outcome in 66 advanced metastatic melanoma (MM) patients treated with subcutaneous IL‐2 in association with interferon‐&agr;, cisplatin and tamoxifen. Our purpose was to correlate the immune modifications during treatment with the clinical response and to define pretreatment factors with predictive value for clinical outcome. The overall response rate was 35%, with a median overall survival of 11.3 months. During treatment, responding patients showed a common marked increase in IL‐12 (mainly released by activated macrophages), sIL‐2R and neopterin serum levels, associated with high levels of total lymphocytes and circulating natural killer lymphocytes; progressing patients were characterized by an increase in IL‐6 serum levels (directly related to the increase in tumour burden). Multivariate analysis showed that high pretreatment IL‐12 levels (P = 0.05) and, to a lesser extent, lactate dehydrogenase levels in the normal range (≤ 450 U/I; P = 0.061) are independent favourable prognostic factors for survival. Our results show that macrophage activation in an immunostimulating way either before or during treatment is associated with a better clinical response and improved survival in advanced MM patients treated with IL‐2‐based chemoimmunotherapy.