•Efficacy of combinations vs sunitinib remain debated in patients with favorable risk.•Favorable risk mRCC patients receiving TKIs as first-line therapy were enrolled.•One metastatic site correlated with longer OS in mRCC patients with good prognosis.•In patients with 1 metastatic site hepatic involvement resulted in worse PFS and OS.•The metastatic site should be considered in the therapeutic choice. Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice. Multicenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups. A total of 107 patients with a median age of 69 years were included in the final analysis. Patients with 1 metastatic site, compared with patients with > 1 site, had a significantly longer overall survival (OS) (not reached vs. 66 months) and a trend, although not statistically significant, of better progression-free survival (PFS) (31 vs. 17 months). In patients with 1 metastatic site, liver involvement was correlated with worse PFS and OS at the univariate analysis (P = .01) and was confirmed as independent poor prognostic factor for PFS at multivariate analysis. In conclusion, we reported a longer OS in favorable risk mRCC patients receiving TKI with only 1 metastatic site. Nevertheless, in patients with a single metastatic site, hepatic involvement correlated with worse PFS compared to other metastatic sites. In this retrospective study, among 107 mRCC patients with favorable risk receiving TKIs, those with 1 metastatic site had significantly longer overall survival and a trend of better progression-free survival compared to patients with > 1 site. Liver involvement was identified as independent poor prognostic factor for PFS. The site of metastases should be considered when choosing therapies for these patients.