Background: It has been reported that the occurrence of immune-related adverse events (irAEs) in oncological patients treated with immune-checkpoint inhibitors (ICIs) may be associated with favorable clinical outcome. We reported the clinical correlation between irAEs and the efficacy of ICIs in a real-world cohort of metastatic renal cell cancer (mRCC) patients. Methods: We retrospectively evaluated 43 patients with mRCC who were treated with nivolumab or with nivolumab plus ipilimumab. We considered seven specific classes of irAEs including pulmonary, hepatic, gastrointestinal, cutaneous, endocrine, rheumatological, and renal manifestations. We assessed progression-free survival (PFS) of specific irAEs classes compared to the no-irAEs group. Results: Twenty-nine out of 43 patients (67.4%) experienced a total of 49 irAEs registered. The most frequent irAE was thyroid dysfunction (n = 14). The median PFS after the beginning of therapy was significantly longer in patients with thyroid dysfunction and cutaneous reactions. In multivariate analysis, thyroid dysfunction was an independent factor for favorable outcome [HR: 0.29 (95% CI 0.11–0.77) p = 0.013]. Moreover, experiencing ≥2 irAEs in the same patient correlated in multivariate analysis with better outcome compared with none/one irAE [HR: 0.33 (95% CI 0.13–0.84) p = 0.020]. Conclusions: This retrospective study suggests an association between specific irAES (thyroid dysfunction and skin reaction) and efficacy of ICIs in metastatic RCC. Notably, multiple irAEs in a single patient were associated with better tumor response.