Survival following prophylactic lymphadenectomy by hip disarticulation in mice with three B16 melanoma variants was studied. C57/BL6 mice inoculated with viable tumor cells (F1, F10, and BL6) into the left hind foot pad were randomized to wide excision (WE) of the primary tumor alone or wide excision plus prophylactic lymphadenectomy (WE plus PL) at 1-, 2-, 3-, 4-, and 5-mm primary tumor sizes (each group, N = 6). Overall survival time was improved by WE plus PL. A significant survival advantage and cure was apparent for the F1 and F10 variants with primary tumor sizes of 2 and 3 mm (F1, 2 and 3 mm, P less than 0.001; F10, 2 mm, P less than 0.006; 3 mm, P less than 0.001), but not for the BL6 variant. Prophylactic lymphadenectomy provides a therapeutic advantage in mouse melanomas of intermediate size in two of the three variants of B16.