OBJECTIVES: The availability of several targeted therapies (TTs) since 2005 has improved survival among metastatic renal cell carcinoma (mRCC) patients. However, their high cost imposes a significant burden on patients and healthcare systems. In order to provide an overview of economic value of TTs, we systematically reviewed cost-effectiveness studies of TTs in the U.S and other countries. METHODS: We searched Medline/PubMed and CINAHL databases using search terms, MeSH and CINAHL headings related to economic analysis and TTs in mRCC. We included original research published in English from the 2005 to 2016. While screening abstracts, we excluded studies unrelated to economic analysis and studies not comparing TTs to a comparator. We reviewed full texts to exclude commentaries, reviews, resource utilization and cost of illness studies. Study quality was assessed using Quality of Health Economic Studies (QHES) instrument. RESULTS: Of 228 studies found during the initial search, we reviewed 15 that met pre-defined selection criteria. Eight studies assessed first-line and 7 assessed second-line therapies. Two of four studies, which compared first-line TTs to cytokine therapy, found TTs to be cost effective (CE) over cytokine therapy. Three studies had direct comparisons of first-line therapies. Sunitinib was CE compared with bevacizumab and sorafenib in U.S and Sweden while pazopanib dominated sunitinib in the U.S and Canada. Five studies compared TTs to best supportive care (BSC). Only sunitinib was CE compared to BSC. Among second-line direct comparisons, everolimus (in the U.S) and axitinib (in Cyprus) were CE compared with sorafenib. Of 15 studies, 12 were good quality studies (QHES-score ≥ 75 of 100) with mean score of 81.8 (SD: ± 10.1). CONCLUSIONS: No drug was CE consistently across all studies. Evidence varied by country and accepted willingness to pay thresholds. Few direct comparisons of first and second-line therapies are available to draw conclusions among targeted therapies.