Background: The development of mutation-directed therapy and immunotherapy has revolutionized the treatment of NSCLC. We investigated outcomes of patients with or without actionable mutations (AM) in relation to their PDL-1 status. Methods: This was a retrospective analysis of patients with stage IV NSCLC from 01/2014 to 06/2022 at our institution. Four groups were identified: P0M0 (PDL-1 <1% and no AM), P0M1 (PDL-1 <1% with AM), P1M0 (PDL-1 ≥1% and no AM), and P1M1 (PDL-1 ≥1% with AM). X² and Wilcoxon rank-rum test were used to assess categorical and continuous data, respectively. Progression-free survival (PFS) and overall survival (OS) were compared between groups using the Cox proportional-hazards model. Results: A total of 117 patients were included. Median age was 65 years, and 63 (54%) were male. The most common histology was adenocarcinoma (79%), followed by squamous cell cancer (14%) and large cell carcinoma (4%). The most common AM was KRAS (22%), followed by EGFR (21%), MET (4%), and HER2 (4%). The median PFS and OS of the entire group were 11.8 and 33.5 months, respectively. Adenocarcinomas had a higher incidence of harboring an AM (62%, p<0.0001). When comparing the PFS and OS with regard to PDL-1 and an actionable mutation, 4 prognostic groups were identified (Table). The P0M0 subgroup (n=24) had the worst median PFS and OS (8.5 and 20.6 months). The P1M1 subgroup (n=41) had the best OS at 44.5 months. Patients in the P0M1 subgroup had a longer PFS than those in the P1M1 subgroup (25.2 vs. 13.1 months), likely due to the presence of more EGFR mutations (57% vs. 32%, p=0.05). However, this did not translate into improved OS (P0M1: 33.5 months, P1M1: 44.5 months, log-rank p=0.98), perhaps because of the durable long-term response to immunotherapy in patients with PDL-1 ≥1%. The results were not significant, likely due to the small sample size in each category. Conclusions: Patients with PDL-1 <1% and no AM had the worst prognosis (median OS, 20 months). Patients with AM and PDL-1 ≥1% had the best OS, 44.5 months. This use of real-world data is an important addition to the existing information to predict survival outcomes of patients with stage IV NSCLC based on the current treatment paradigm. It provides important clinical information and should be corroborated in a larger study.