Metastatic spread of solid tumors depends on a complex metastatic cascade. Metastatic tumor cells must therefore express a variety of biological properties including the ability to proliferate and the ability to migrate. In the present study, the prognostic significance of both parameters was investigated in 184 cases of malignant melanoma of the skin. Proliferative activity was assessed by mitotic counts, the degree of cell motility was estimated by comparing the histological pattern of the tumor with patterns obtained by computer simulations with predefined values of cell motility. Follow up of surviving patients was at least 5 years. Statistical analysis was done using classification and regression tree (CART) analysis combining mitotic counts and motility estimates. As far as overall survival was concerned, mitotic counts were the most significant variable separating one group of patients with mitotic counts < 17/mm2 and a 5-year survival rate of 82% and a group with mitotic counts > or = 17/mm2 and a 5-year survival rate of 52%. Within the group with low mitotic counts, motility estimates found a subgroup of patients with a coefficient of motility > or = 126, which had a 5-year survival rate of 55% similar to those patients with high mitotic counts. Corresponding results were obtained in the assessment of metastasis-free interval. The data show that not only proliferation as assessed by mitotic counts, but also estimates of tumor cell motility based on image analysis and computer simulations provide prognostic information in primary malignant melanoma of the skin.