In this retrospective study we focused on a subgroup of rare tumors, such as non–clear-cell renal cancers, with the aim to provide evidence of activity and feasibility of a multityrosine kinase inhibitor, pazopanib, as a first-line treatment alternative to the widely used sunitinib. Our conclusions support the use of pazopanib in this subgroup, awaiting prospective results of ongoing clinical trials. Introduction Pazopanib is a standard first-line treatment for metastatic clear-cell renal cell carcinoma (ccRCC). Very few data on its activity in non–clear-cell renal cell carcinoma (nccRCC) are currently available. The aim of this study was to retrospectively analyze efficacy and toxicity of pazopanib in nccRCC patients. Patients and Methods Records from advanced nccRCC patients (consecutive sample) treated with first-line pazopanib between 2010 and 2015 at 17 Italian centers were reviewed. Response rate, progression-free survival (PFS), and overall survival (OS) were evaluated. Univariate and descriptive analyses were performed. Results Thirty-seven patients with nccRCC were treated with first-line pazopanib; 51% had papillary histology, 24% chromophobe, 22% unclassified, and 3% had Xp11.2 translocation. Dose reductions/temporary interruptions for toxicity were required in 46% of cases. Grade (G) 3/4 toxicity was seen in 32%, G1/2 in 89% of cases; 81% achieved disease control, with 10 partial responses (27%) and 20 cases of stable disease (54%); 16% of patients had disease progression as best response. Median PFS and OS were 15.9 and 17.3 months, respectively. In univariate analysis, nephrectomy (P = .020), Memorial Sloan Kettering Cancer Center (MSKCC) score (P < .001), basal neutrophil/lymphocyte ratio (NLR; P = .009) and performance status (PS) (P = .001) were associated with PFS; MSKCC score (P < .001), International Metastatic Renal Cell Carcinoma Database Consortium score (P = .003), PS (P < .0001), nephrectomy (P = .002), histology (P = .035), dose reductions/interruptions (P = .039), best response to treatment (P < .001), and NLR (P = .008) were associated with OS. Conclusion In nccRCC patients, treatment with pazopanib was effective and feasible; dose reductions required for toxicity were similar as expected in ccRCC. © 2016 Elsevier Inc.