Background: Immune checkpoint inhibitors (ICIs) improve survival outcomes in metastatic melanoma and non-small cell lung cancer (NSCLC). Preclinical evidence suggests that overexpression of cyclooxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 production and that COX inhibition synergizes with ICIs to promote antitumor T-cell activation. This study investigates whether concurrent COX inhibitor (COXi) use during ICI treatment is associated with improved time-to-progression (TTP), objective response rate (ORR) and overall survival (OS) in metastatic melanoma and NSCLC patients. Methods: We retrospectively reviewed 90 metastatic melanoma and 37 metastatic NSCLC patients, treated only with ICI between 2011 and 2019. Differences in TTP and OS by COXi use were compared using Kaplan-Meier and Cox regression. Interaction between COXi use and neutrophil-lymphocyte ratio (NLR) was examined. Independent radiology review per RECIST v1.1 was performed. Results: For melanoma patients, median TTP was significantly prolonged in COXi users (245 v 100.5 days, p = .0002). On multivariate analysis (MVA), COXi use associated with increased TTP (HR 0.36, 95% CI: 0.2 – 0.66, p = 0.001) when adjusted for age, pretreatment NLR, and gender. For NSCLC patients, COXi use also associated with increased TTP on MVA (HR 0.45; 95% CI: 0.21 – 0.97; p = 0.042) adjusted for age. ORR at 6-months was significantly higher in patients who received concurrent COXi compared to those that did not in both melanoma (58.6% v 19.2%, p = 0.0005) and NSCLC (73.7% v 33.3%, p = 0.036) cohorts. COXi use was associated with improved OS in NSCLC patients on MVA (HR 0.3; 95% CI: 0.12 – 0.78; p = 0.013), but not in melanoma patients. In the melanoma cohort, high pretreatment NLR of > 5 associated with decreased TTP on MVA (HR 3.21, 95% CI: 1.64 – 6.3; p = 0.0007). However, for melanoma patients with high NLR > 5, COXi use significantly associated with increased TTP (HR 0.08, 95% CI: 0.03 – 0.25); but in melanoma patients with low NLR ≤5, there was no effect on TTP (HR 0.65, 95% CI: 0.32-1.32). Similar outcomes were found in an adjusted melanoma cohort after RECIST review. Conclusions: Our study suggests that use of COXi concurrent with ICI is significantly associated with longer TTP and improved ORR at 6-months in metastatic melanoma and NSCLC patients. NSCLC patients using COXi had prolonged OS. Furthermore, COXi use appears to reverse the negative prognostic effect of a high NLR by prolonging TTP in melanoma patients.