Background: Immune checkpoint inhibitors (ICI) have significantly improved outcomes in non-small cell lung cancer (NSCLC) but are associated with development of immune related adverse events (irAEs). Currently, the role of germline determinants on immunotherapy efficacy and toxicity is unclear. Human leukocyte antigen (HLA) is emerging as a possible predictive biomarker. Our study aimed to assess HLA class II genotypes and their correlation to irAEs and survival. Methods: We conducted a single institution, prospective study with collection of baseline blood samples in patients with metastatic NSCLC treated with ICIs. Clinical characteristics and HLA genotypes (ScisGo HLA typing kits) were obtained. Kaplan-Meier method was used to calculate progression free survival (PFS) and overall survival (OS). Cox regression model was used for multivariate analysis (MVA) and we adjusted for age, gender, race, stage, and histology. Cumulative incidence function was used for association between HLA-DRB4 and endocrine irAEs. Results: Among 98 eligible patients, 85 had complete HLA genotyping. Most patients were men (96.5%), Caucasian (75.3%), and former/active smokers (98.8%) with a median age of 72 years. Median follow up time was 42.8 months. Majority of patients received pembrolizumab (83.5%). Other ICIs included durvalumab (10.6%) and nivolumab (4.7%). Twenty patients (23.5%) experienced irAEs – 11 patients had endocrine irAEs and 9 with other irAEs. 3 patients (27.3%) with endocrine irAEs had toxicity grade 3. Presence of irAE did not improve PFS (p = 0.226, HR 0.61, 95% CI [0.268,1.365]) or OS (p = 0.219, HR 0.63, 95% CI [0.301,1.316]). HLA-DRB4 was present in 39/85 patients (45.9%) and was the predominant genotype in patients with endocrine irAE (9/11, 81.8%) (Table 1). The cumulative incidence of endocrine irAEs was higher in patients expressing HLA-DRB4 (p = 0.0139). HLA-DRB4 improved survival in both univariate (PFS 9.9 months, p = 0.040; OS 26.3 months, p = 0.0085) and MVA (PFS p = 0.0310, HR 0.55, 95% CI [0.31, 0.95]); OS p = 0.003, HR 0.40, 95% CI [0.21, 0.73]). Conclusions: Expression of HLA-DRB4 was associated with the development of endocrine irAEs and correlated with improved survival outcomes in metastatic NSCLC patients being treated with ICIs. Further studies are necessary to validate our findings of HLA-DRB4 as a possible predictive marker for endocrine irAEs and therapy efficacy.