Background: Older age is associated with increased levels of systemic inflammation and altered immunosurveillance in cancer. Whether aging correlates with a distinct immunophenotype or impacts clinical outcomes to first-line pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of ≥50% is unclear. Methods: We performed a retrospective analysis of patients with NSCLC. Multiplexed immunofluorescence (mIF) for CD8+, PD-1+, PD-1+CD8+ and FOXP3+ was performed to explore tumor immunophenotype. Clinical outcomes were analyzed on a separate cohort of patients with PD-L1-high (TPS of ≥50%) NSCLC (negative for sensitizing genomic alterations in EGFR and ALK) who received treatment with first-line pembrolizumab. Variables demonstrating a univariate signal of association of p < 0.1 were included in the multivariate model. The results were compared in patients < 80 vs ≥80 years old. Results: Among 541 patients with NSCLCs profiled by mIF, the median age was 67 (28-90). When comparing patients < 80y (n = 497) to ≥80y (n = 44), there was no difference in median CD8+ T cells/mm2 (171 vs 148; p = 0.69), PD-1+ immune cells/mm2 (81.1 vs 87.2; p = 0.95), or PD-1+CD8+ T cells/mm2 (18.0 vs 13.1; p = 0.56). NSCLCs from patients ≥80y had a higher median of intratumoral-associated FOXP3+ T cells/mm2 (63.6 vs 91.1; p = 0.03). In a cohort of 271 patients with PD-L1 ≥50% who received first-line pembrolizumab, baseline clinicopathological characteristics were balanced in the < 80y (n = 225) vs ≥80y (n = 46) groups in terms of sex, tobacco use, Eastern Cooperative Oncology Group-Performance Status (ECOG-PS), histology, presence of potentially targetable driver mutations (KRAS, MET, BRAF, HER2, RET), and PD-L1 TPS distribution (50-89% vs ≥90%). Compared to patients < 80y, patients ≥80y had no difference in objective response rate (ORR 39.1% vs 28.2%; p = 0.22) or median progression-free survival (mPFS 6.0 vs 3.0 months; p = 0.16). However, patients ≥80y had a shorter median overall survival (mOS 25.7 vs 7.6 months; p = 0.02), and this result remained significant after adjusting for ECOG-PS. Among those who experienced disease progression on pembrolizumab, patients ≥80y were significantly less likely to receive any second-line systemic therapy compared to patients < 80y (55.6% vs 30.8%; p = 0.008). Conclusions: In patients with NSCLC and PD-L1 ≥50%, the ORR and mPFS to first-line pembrolizumab were similar between patients < vs ≥80 years old. OS was shorter among patients ≥80y, potentially reflecting lower use of second-line therapy in elderly patients after progression on pembrolizumab. The immunophenotypic correlates of NSCLC in older patients need further investigation.