Abstract Purpose: Programmed cell death receptor-1 (PD-1) inhibitors are frontline therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti–PD-1 monotherapy remains unclear. Experimental Design: In this multicenter retrospective analysis, patients treated with anti–PD-1 monotherapy between 2009 and 2019 and detailed GCC use, data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti–PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed. Results: Of the entire cohort of 947 patients, 509 (54%) developed irAEs. In the MGH cohort [irAE(+) n = 90], early-onset irAE (within 8 weeks of anti–PD-1 initiation) with high-dose GCC use (≥60-mg prednisone equivalent once a day) was independently associated with poorer post-irAE PFS/OS (progression-free survival/overall survival) [post-irAE PFS: HR, 5.37; 95% confidence interval (CI), 2.10–13.70; P < 0.001; post-irAE OS: HR, 5.95; 95% CI, 2.20–16.09; P < 0.001] compared with irAEs without early high-dose GCC use. These findings were validated in the combined validation cohort [irAE(+) n = 419, post-irAE PFS: HR, 1.69; 95% CI, 1.04–2.76; P = 0.04; post-irAE OS: HR, 1.97; 95% CI, 1.15–3.39; P = 0.01]. Similar findings were also observed in the 26-week landmark analysis for post–irAE-PFS but not for post–irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results. Conclusions: Early high-dose GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti–PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.