Background: In patients with RET-rearranged lung cancers, multikinase inhibitors (e.g. cabozantinib and vandetanib) and specific (e.g. pemetrexed-containing) chemotherapy regimens have documented activity. In contrast, PD-L1 expression, tumor mutational burden (TMB), and the treatment outcomes of immunotherapy are not well characterized in this genomic subset. Methods: Patients with a pathologically confirmed diagnosis of lung cancer harboring a RET rearrangement were identified between January 2012 and December 2017. PD-L1 expression was determined by IHC (E1L3N Clone). TMB was calculated in tumors that underwent NGS (Mutations/Mb, MSK-IMPACT). Objective response rate (ORR) to immunotherapy was evaluated by RECIST. Results: 74 patients with RET-rearranged lung cancers were identified. The median age was 63 (range 34-80 years), 55% were women, and 68% were never smokers. The majority (97%) had adenocarcinoma and 85% had metastatic disease. In patients with sufficient tissue for analysis, tumor PD-L1 expression was as follows: PD-L1 ≥50% in 21% (5/24, 95% CI 5-37%), PD-L1 1-49% in 25% (6/24, 95% CI 8-42%), and PD-L1 0% in 42% (13/24, 95% CI 22-62%). The median TMB of RET-rearranged lung cancers was 3.3 Mt/Mb (range 0.82-9.84, n = 43) and lower than the median TMB of 5.7 Mt/Mb in unselected NSCLCs (n = 1,769, p < 0.001). 12 patients received PD-1/PD-L1 blockade and 1 patient received 2 lines: pembrolizumab (6), nivolumab (4), atezolizumab (2), and durvalumab (1). ORR by RECIST was 0% (0/5 evaluable). The median duration of therapy was 1.4 months (m) (range 0.5-8.7m). Responses were not enriched in those with positive PD-L1 expression (≥1%) nor in those with TMB > median of all NSCLCs. The overall survival of patients who received immunotherapy did not differ from patients who did not receive immunotherapy (n = 51): 18.2 vs 17.9m, p = 0.6. Conclusions: While PD-L1 expression occurs in a substantial proportion of RET-rearranged lung cancers, TMB is lower compared to unselected lung cancers, and response to immunotherapy is poor. RET-directed targeted therapy strategies and platinum doublet chemotherapy should be considered prior to single-agent immunotherapy.