Background: Tissue PD-L1 protein expression is predictive of immune checkpoint inhibitor (ICI)-based treatment outcomes in advanced non-small-cell lung cancer (aNSCLC). However, tissue PD-L1 can be fraught with tissue acquisition difficulties and tumor heterogeneity. Plasma cell-free RNA (cfRNA) PD-L1 expression assessed with a liquid biopsy potentially overcomes these tissue limitations and could identify additional patients likely to benefit from ICI therapy. Outcome studies validating this novel approach have not been previously reported. Methods: An observational cohort of patients with aNSCLC treated in an academic medical center with 1^st-line ICI-based therapies were retrospectively evaluated for a pre-planned endpoint of overall survival (OS) based upon plasma cfRNA PD-L1 expression by a proprietary exosome-free real-time qPCR assay and/or tissue PD-L1 protein expression (Dako 22C3) performed in commercial CLIA/CAP accredited laboratories. Results: Of 75 consecutive aNSCLC patients, 16 (21.3%) were plasma cfRNA PD-L1 positive expression with 6 of these 16 (37%) tissue PD-L1 negative or quantity not sufficient. 35 patients were both tissue and plasma PD-L1 negative and 24 patients tissue PD-L1 positive but plasma PD-L1 negative. Median follow-up 34 months. The plasma PD-L1 or tissue PD-L1 positive patients demonstrated no difference in OS outcomes (median OS 16 months; 3-year landmark OS 30%; hazard ratio (HR) 0.97; 95% CI, 0.44-2.10). The plasma PD-L1 positive patients demonstrated superior OS outcomes compared to tissue and plasma PD-L1 negative patients (median OS 16 months versus 8 months; landmark 3-year OS 30% versus 20%; HR 0.59; 95% CI, 0.31-1.11). The plasma PD-L1 positive patients demonstrated no differing OS outcomes whether tissue PD-L1 positive or negative (median OS 13-16 months; 3-year landmark OS 30%; HR 1.15; 95% CI, 0.32-4.05). Conclusions: In this single-institution aNSCLC patients receiving 1^st-line ICI therapy OS outcomes were the same for plasma PD-L1 positive patients vs. tissue PD-L1 positive patients. OS outcomes were superior for patients with positive plasma PD-L1 expression vs. similarly treated patients negative for tissue PD-L1 or plasma PD-L1 expression. In patients with plasma cfRNA PD-L1 expression, there was no OS differences whether tissue PD-L1 protein was positive or negative, suggesting that liquid biopsy might identify additional patients who could benefit from ICI therapy.