Introduction: Sarcomas are rare cancers, consisting of a variety of subtypes. In general, standard of care is surgery sometimes combined with traditional chemotherapy and/or radiotherapy. Clinical outcome is poor, and there is a critical need for new therapeutics. Recently, the B-RAFV600E mutation was found in several sarcomas by next generation sequencing. Several inhibitors targeting the B-RAFV600E mutation are approved for clinical treatment of metastatic melanoma, opening for drug repurposing and a personalized medicine approach. In this study, we investigated the preclinical efficacy of targeting B-RAFV600E mutations in sarcoma cell lines with the two drugs vemurafenib (B-RAFV600E-selective inhibitor) or RO5126766 (inhibitor of all RAF isoforms and MEK1 kinase). Methods: Two liposarcoma cell lines (SA-4 and SW872), one synovial sarcoma cell lines (SW982) and one Ewing’s sarcoma cell line (A673) were found to express the B-RAFV600Emutation. Response to targeted therapy was evaluated by monitoring effects on cell growth. The effect on the responding cell line SA-4 was further elucidated by apoptosis assay, cell cycle analysis and drug removal assays. Two B-RAFV600E mutated melanoma cell lines (A375 and WM9) and one liposarcoma (LPS510) without the mutation were included as control cell lines. Results: Vemurafenib and RO5126766 induced significant growth inhibition of the SA-4 cell line. Furthermore, although vemurafenib induced apoptosis in a subset of SA-4 cells, a G1-cell arrest appeared to be the main mechanism for growth inhibition in these cells during short-term treatment. In addition, the SA-4 cells were able to regrow following removal of vemurafenib indicating a reversible inhibitory effect. For the remaining sarcoma cell lines, a minor growth inhibition was observed following treatment with either inhibitor, indicating a resistance to therapies targeting B-RAFV600E proteins. Conclusion: SA-4 was the sarcoma cell line with the greatest response to B-RAF inhibition. However, the growth inhibitory effect was reversible following removal of vemurafenib. The other three B-RAF mutated sarcoma cell lines analyzed in the study displayed only a minor response to either inhibitor. The lack of response indicates that these three cell lines are not dependent solely on the MAPK pathway for cell growth. The search for effective targeted therapy should therefore extend to other essential pathways or cellular mechanisms essential for sarcoma progression.