Background: We investigated the prognosis of Japanese mRCC patients with favorable or intermediate MSKCC risk factors in the era of molecular targeted therapy Methods: Data on patients who started systemic therapies including cytokine and molecular targeted therapies at 18 hospitals between 2008 and 2010 was analyzed. Of these, 269 patients classified as favorable or intermediate prognosis according to MSKCC risk classification were the subject of this analysis. The endpoints of the present study were progression-free survival (PFS) and overall survival (OS). Relationships between PFS or OS and clinical variables were assessed using the Cox-proportional hazard model. Results: The median OS of all 268 patients was 38 month, and 3-year OS rate was 51% (95%CI 45-58). Regarding the first-line therapy, IFN-alfa (IFN), sunitinib (SU), sorafenib (SO), and others were administered in 89 (33%), 104 (39%), 40 (15%), and 35 (13%). There were more patients without nephrectomy and with multiple organ metastases in patients received SU or SO compared to patients received IFN. Median PFS (mPFS) and 1-year PFS rate in patients who received IFN, SU, and SO were 5 months and 38%, 12 months and 50%, and 11 months and 48% (p=0.556), respectively. Second-line therapy was performed in 69 patients of first IFN group (mPFS: 9 months), 67 of first SU group (mPFS: 7 months), and 24 of first SO group (mPFS: 3 months). Third-line therapy was performed in 47 patients of first IFN group (mPFS: 11months), 35 of first SU group (mPFS: 5 months) and 12 of first SO group (mPFS 3 months). Median OS in patients who received IFN, SU, and SO as first-line therapy were 45, 29 and 27 months (p=0.093), respectively. Multivariate analysis demonstrated that lower value of serum C-reactive protein and first IFN therapy were associated with more favorable OS (p<0.05). Conclusions: In Japanese mRCC patients with favorable or intermediate MSKCC risk factors, first IFN therapy would still be appropriate even in the era of molecular targeted therapy. Furthermore, more potent sequential strategy after first molecular targeted therapy should be established for the improvement of OS.