Background: The effect of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on immune checkpoint inhibitor (ICI) antitumor activity is not well-known. We compared tumor outcomes of patients who received corticosteroid monotherapy versus those who received an addition of SSIA for irAE treatment. Methods: We conducted a retrospective case-control study of patients age ≥18 years with melanoma or non-small cell lung cancer (NSCLC) who were treated with ≥1 ICI at a quaternary care center between 1/1/2016-11/1/2021. Patients must have received systemic corticosteroids or an SSIA for irAE treatment at least 1 week prior to death. Patients were divided into two cohorts: only corticosteroids (CS cohort) or steroids+SSIA (SSIA cohort). We used propensity score nearest-neighbor matching to match on tumor type, stage, and prior lines of therapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included time from start of irAE treatment to irAE resolution. Hazard ratios (HR) for PFS and OS were calculated using the Cox proportional hazard regression method with time to steroid and SSIA as a time-varying covariate. Results: After matching, 48 patients were included, 24 in each cohort. Median age was 65. 41.7% of patients had NSCLC and 58.3% melanoma, 79.2% had stage 4 disease. 62.5% received ICIs as first line therapy, 33.3% as second-line, and 4.2% as third-line or higher. There was no significant demographic difference between the cohorts. Colitis was the most common irAE (39.6%). After adjusting for age, tumor type, tumor stage, and weeks from ICI start to steroid start, patients in the SSIA cohort had a shorter OS (HR 2.31, p = 0.037). We did not find a statistically significant difference for PFS (unadjusted HR 0.52, p = 0.20; adjusted HR 0.62, p = 0.34). Time from irAE treatment to resolution was longer in the SSIA cohort (8.1 weeks) compared to the CS cohort (4.9 weeks), but this did not reach statistical significance (p = 0.07). Conclusions: We found an association between decreased OS and use of SSIAs for irAE treatment compared to CS monotherapy, but no significant difference in PFS between the two cohorts. Large, prospective, randomized controlled trials are needed to separate the effects of SSIAs from high-dose CS in order to guide optimal treatment of irAEs.