ObjectivesTo compare five molecular targeted drugs (MTD) with interferon-α (IFN-α) and evaluate their clinical efficacy and adverse events as first line therapy for metastatic renal cell carcinoma (mRCC).MethodsWe conducted a systemic review and network meta-analysis of all relevant randomized controlled trials (RCTs) assessing MTD and IFN-αthrough a comprehensive search of databases including PubMed, Science Direct, Embase and Cochrane Library databases from January 2005 to April 2014.ResultsEight articles with 4,718 patients were finally identified. No statistically significant difference existed between direct and indirect evidences and the convergence of analysing model was guaranteed. With INF-αas baseline, the OR values of five MTD (pazopanib, axitinib, bevacizumab + INF-α, sunitinib, sofafenib) in terms of objective response rate (ORR), were separately: 4.00, 95% CI, 0.25-52.88); 3.46, 95% CI, 0.16-52.20); 3.21, 95% CI, 0.84-12.79); 2.94, 95% CI, 0.55-12.81); 1.18, 95% CI, 0.17-6.63). When it comes to adverse events, the OR values and 95% CI of 5 MTD (sunitinib, bevacizumab + INF-α, axitinib, pazopanib, sofafenib) were separately: 3.65, 95% CI, 0.65-20.32; 3.22, 95% CI, 0.71-16.06; 1.77, 95% CI, 0.07-47.59; 1.45, 95% CI, 0.08-31.05; 0.65, 95% CI, 0.09-4.25. The probabilities of being the most efficacious treatments in terms of ORR were: pazopanib (37%), axitinib (34%), bevacizumab + IFN (21%), sunitinib (8%), sorafinib (1%) and IFN (0%). The probabilities of having least ≥ grade 3 adverse events were: sorafenib (52%), pazopanib (18%), IFN-α (17%), axitinib (11%), bevacizumab + IFN-α (1%), sunitinib (0%).ConclusionsMTD was found to be superior to IFN-α in ORR but possessed of more ≥ grade 3 adverse events as first line treatment for patients with mRCC. Pazopanib, an oral MTD, was identified as a relatively rational choice. More well-designed and qualified trials are required to confirm these findings and investigate the clinical effective of MTD for the treatment of mRCC.