We studied the patterns of spontaneous regional lymph node metastases of three variants (F1, F10, and BL6) of the B16 melanoma in C57BL/6 mice and related the incidence to primary tumor size and pulmonary metastases. The incidence of regional lymph node and pulmonary metastases correlated with increasing primary tumor size (p less than or equal to 0.0001). The incidence of pulmonary metastases in mice whose regional lymph nodes did not contain tumor also correlated with increasing primary tumor size (p less than or equal to 0.0001). This propensity for direct hematogenous spread was more apparent in BL6 tumors than in F1 and F10 tumors (p less than or equal to 0.0001). BL6 tumors also metastasized to regional nodes at smaller primary tumor sizes (p less than or equal to 0.04). Heterogeneous variants that metastasize earlier to regional lymphatic and hematogenous sites dictates the natural history of the primary tumor. Whether prophylactic lymphadenectomy for melanomas is therapeutic may depend on dissemination-related phenotypic characteristics.