Spontaneous regression occurs in a small proportion of malignant melanomas, and it is important to understand the processes involved in its induction as this may give a guide to future therapies for this disease. We have examined 36 primary malignant melanomas (19 regressing, 17 non-regressing) and identified the cellular phenotypes and activation states of the cells infiltrating regressing and non-regressing primary melanomas by immunochemistry. We have found a significantly increased number of CD3-positive cells and an increased ratio of CD4/CD8-positive cells infiltrating regressing compared to non-regressing tumors. In addition, the expression of the interleukin 2 receptor, an activation marker for T cells, was increased. However, there were no significant differences in class II MHC, CD1, intercellular adhesion molecule 1 (ICAM1), or melanoma-associated differentiation-antigen expression in these tumors. These data are consistent with melanoma regression being induced by activated CD4 T cells and do not seem to be related to the differentiation markers we have examined on these tumors.