Malignant melanoma is the most lethal skin cancer with no effective therapeutic treatment in its metastatic stages. RAS and PI3K pathways have been shown to play a critical role in melanoma development and progression. In this study, we assessed the in vitro and in vivo inhibition potential of a BRAF inhibitor (Sorafenib, Bayer) and a PI3K/mTOR inhibitor (PI-103, PIramed-Genentech) in primary melanoma cell lines. We used primary cell lines isolated from spontaneous melanomas obtained in the UV induced HGF transgenic melanoma mouse model.Although PI-103 and sorafenib inhibited melanoma in vitro cell proliferation and viability, the inhibition of RAS pathway was more effective. The combination of the two drugs showed a synergistic effect inhibiting RAS and PI3K pathways and in vitro melanoma cell proliferation in a cell line dependent manner. However, the combined treatment of orthotopic xenographs in immunocompetent FVB mice did not cooperate blocking tumor growth. Surprisingly, the in vivo treatment with PI-103 enhanced tumor growth. Our results also revealed that PI-103 caused immunosuppression inducing thymus atrophy and upregulating the intratumoral transcriptional levels of inmunosuppressors. In addition, PI-103 induced the antiapoptotic BH3 family proteins Mcl-1, Bcl-2 and BclXL, which correlated with the lower apoptotic rate observed within the PI-103 treated tumors. These data indicates that due to melanoma heterogeneity, some precautions should be taken when using these inhibitors for treatment. Moreover, these results certainly make an argument for investigating unexpected effects of rational drug combinations on immunocompetent animal models before conducting clinical studies.