In order to clarify the role of tyrosinase (E.C. 1.14.18.1) in the cytotoxicity of 4‐hydroxyanisole (4HA) in vivo, we have compared the therapeutic effects of 4HA on the B16 melanoma and Harding‐Passey melanoma, which differ significantly in their tyrosinase content. The observed therapeutic effects are moderate and similar in both tumors. Therefore, there is no evidence for an increase of the cytotoxic effect of 4HA by tyrosinase in vivo. Application of 4HA to mice carrying B16 melanoma and Harding‐Passey melanoma results in an inhibition of [3H]‐TdR incorporation into melanoma DNA as well as into DNA of liver, intestine, kidney, and spleen. There is no selective activity on melanoma cells by 4HA in vivo. Therefore, in the therapy of human melanoma by 4HA, side effects on normal tissues cannot be e