The potential therapeutic efficacy of TP5 in patients with cutaneous and subcutaneous metastases of melanoma was tested in a double-blind study comparing the drug and placebo injected perinodularly. Of the 47 nodules present in the 16 patients treated with TP5, 24 showed a measurable response, whereas only one out of 15 nodules in patients treated with a placebo showed a minor response (P = 0.02). In two patients treated with TP5 a response of two nodules not perinodularly injected was also observed. Sclerosis, CD45RO+ cells and MIB 1− cells were more frequently observed in nodules treated with TP5 than with placebo. (P = 8 ± 10−4; 0.03 and 0.01, respectively). Evaluating the trends of these findings in nodules treated with placebo; with TP5-treated, non-responding nodules; or with TP5-treated, responding, a positive trend was observed for sclerosis and CD45RO+ cells (P = 5 ± 10−4 and 2 ± 10−3, respectively) and a negative one for MIB 1 cells (P = 2 ± 10−3). These preliminary data suggest that lymphoid cells associated with nodules regression are activated large lymphocytes (CD45RO+ and CD3−). Sclerosis might be Interpreted as the final morphologic event, and reduction of proliferative activity (MIB 1- cells) as the conseqence of cytolytic action.