In melanoma development and progression, PDGF has been suggested to modulate the microenvironment, especially stromal fibroblasts, to the benefit of melanoma growth, invasion, and metastasis. Lycopene, a natural carotenoid that is abundant in tomato, has been shown to inhibit proliferation of several types of cancer cells. However, little attention has been paid on melanoma and skin fibroblast cells. In the present study, we determined the effects of lycopene on stromal fibroblasts. We found that lycopene inhibited PDGF-induced human Hs68 skin fibroblast migration on gelatin and collagen. Further analysis showed that lycopene inhibited PDGF-BB-induced signaling in human Hs68 and cultured skin fibroblasts. PDGF-BB-induced phosphorylation of PDGF receptor, ERK1/2, p38, and JNK was attenuated by lycopene, whereas the expression of each total protein was not affected, suggesting that lycopene has relative specificity on PDGF-BB-induced signaling. Surprisingly, dot binding assay indeed demonstrated that lycopene could directly bind to human PDGF-BB in a dose-dependent manner, suggesting that lycopene acts on PDGF-BB rather than on fibroblasts. In the parallel experiments, lycopene inhibited melanoma-induced fibroblast migration in a non-contact coculture system and attenuated signaling transduction pathway in fibroblasts simulated by melanoma-derived conditioned medium. Our results suggest that lycopene is an effective inhibitor on migration of the stromal fibroblasts and this effect may contribute to its anti-tumor activity.