Vemurafenib is a B-raf inhibitor which is widely used in treatment of melanoma patients with B-RAF V600E mutation. Majority of patients treated with vemurafenib develop resistance against the drug. Here, we asssessed the effectiveness of a combination drug therapy in vemurafenib resistant melanoma cells. Vemurafenib resistant A375 melanoma cells (A375Res cells) were developed by growing parental cells in increasing concentrations of the drug. The A375Res cells were 50 times more resistant (higher IC50 value), had reduced cell doubling time, were less responsive to the antiproliferative activity of Vemurafenib and showed increased tumor forming potential as compared to the parental cells. Vemurafenib inhibited phosphorylation of MEK 1/2 and ERK 1/2 at the concentrations far less than those that were effective in parental cells. Compared to the other drugs sorafenib in combination with vemurafenib significantly inhibited proliferation of A375Res cells. These findings show that Sorafenib, in combination with Vemurafenib, is a more effective method for treatment of melanoma with B-Raf 600E mutation.