Background/Objectives: Anti–PD-1/PD-L1 blockers have revolutionized the treatment landscape of non–small cell lung cancer (NSCLC) lacking oncogene-addicted alterations, particularly in tumors with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%). Cemiplimab is approved as first-line monotherapy in this setting. However, real-world data remain scarce. This study aimed to evaluate the efficacy and safety of single-agent cemiplimab in a multicenter Spanish cohort and compare outcomes with a historical pembrolizumab cohort. Methods: Cemi-SPA is a retrospective multicenter study including 150 patients with advanced NSCLC and PD-L1 ≥ 50% treated with cemiplimab as first-line monotherapy across 21 Spanish centers. Clinical outcomes were analyzed and compared with a historical cohort of 144 patients treated with pembrolizumab. Propensity score matching (PSM) was performed to adjust for baseline differences. Results: Median progression-free survival (PFS) and overall survival (OS) were 8.1 and 12.6 months, respectively. ECOG performance status ≥ 2 was independently associated with worse outcomes, whereas the development of immune-related adverse events correlated with improved PFS and OS. After PSM, no significant differences were observed between cemiplimab and pembrolizumab in terms of efficacy. Conclusions: Cemiplimab demonstrated comparable real-world efficacy and safety to pembrolizumab in patients with advanced NSCLC and PD-L1 ≥ 50%. ECOG performance status emerged as the strongest prognostic factor, highlighting the importance of patient selection in routine clinical practice.