Background: Pembro monotherapy was approved in the US in October 2016 as 1L therapy for patients with metastatic NSCLC and PD-L1 tumor proportion score (TPS) ≥50% based on findings from KEYNOTE-024. With 5-year follow-up in KEYNOTE-024, median overall survival (OS) was 26.3 months (95% CI, 18.3–40.4) in the pembro arm. With 4-year follow-up in KEYNOTE-042, median OS was 20.0 months (15.9–24.2) in the pembro PD-L1 ≥50% subgroup. Our aim was to describe long-term, real-world outcomes with 1L pembro monotherapy for patients treated at US oncology practices with disease characteristics similar to those in the KEYNOTE trials. Methods: Patients initiating 1L pembro monotherapy from December 1, 2016, through November 30, 2017, were selected from the US nationwide Flatiron Health de-identified, electronic health record-derived database if they had stage IV or recurrent metastatic NSCLC with PD-L1 TPS ≥50%, ECOG performance status 0–1, and no known EGFR/ALK/ROS1 aberration (confirmed negative EGFR/ALK for nonsquamous tumors). Enhanced manual chart review was used to determine real-world progression (rwP), tumor response (rwTR), and reasons for pembro discontinuation. OS and real-world progression-free survival (rwPFS) were estimated using the Kaplan-Meier method. Data cutoff was August 31, 2020. Results: Median study follow-up was 38.4 months (range, 33.1–44.9). Of 228 eligible patients, median age was 71 years (range, 46–82); 123 (54%) were women; 156 (68%), 12 (5%), and 60 (26%) had nonsquamous, not otherwise specified, and squamous NSCLC, respectively; and 209 (92%) were current/former smokers. History of brain metastasis was recorded for 17 (7%). Pembro was discontinued by 151 patients (66%), most commonly because of disease progression (70; 46%) and secondarily for toxic effect of therapy (35; 23%); 87 patients (38%) received ≥1 additional lines of therapy. OS, rwPFS, and rwTR results are shown below. Conclusions: In this real-world study with 3-year follow-up, patients with PD-L1 TPS ≥50% metastatic NSCLC without known EGFR/ALK aberrations and good performance status treated with 1L pembro monotherapy experienced median OS of 23 months, similar to the OS observed in phase III pivotal clinical trials, supporting the long-term OS benefits of 1L pembro monotherapy in this patient population.