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Background: Programmed death ligand‐1 (PD‐L1) expression is a well‐known predictive biomarker of response to immune checkpoint blockade in non‐small cell lung cancer (NSCLC). However, there is limited evidence of the relationship between PD‐L1 expression, clinicopathological features, and their association with major driver mutations in NSCLC patients in Latin America. Methods: This retrospective study included patients from Argentina with advanced NSCLC, and centralized evaluation of PD‐L1 expression concurrently with genomic alterations in the driver genes EGFR, ALK, ROS1, BRAF, and/or KRAS G12C in FFPE tissue samples. Results: A total of 10 441 patients with advanced NSCLC were analyzed. Adenocarcinoma was the most frequent histological subtype (71.1%). PD‐L1 expression was categorized as PD‐L1 negative (45.1%), PD‐L1 positive low‐expression 1%–49% (32.3%), and PD‐L1 positive high‐expression ≥50% (22.6%). Notably, current smokers and males were more likely to have tumors with PD‐L1 tumor proportion score (TPS) ≥50% and ≥ 80% expression, respectively (p < 0.001 and p = 0.013). Tumors with non‐adenocarcinoma histology had a significantly higher median PD‐L1 expression (p < 0.001). Additionally, PD‐L1 in distant nodes was more likely ≥50% (OR 1.60 [95% CI: 1.14–2.25, p < 0.01]). In the multivariate analysis, EGFR‐positive tumors were more commonly associated with PD‐L1 low expression (OR 0.62 [95% CI: 0.51–0.75], p < 0.01), while ALK‐positive tumors had a significant risk of being PD‐L1 positive (OR 1.81 [95% CI: 1.30–2.52], p < 0.01). Conclusions: PD‐L1 expression was associated with well‐defined clinicopathological and genomic features. These findings provide a comprehensive view of the expression of PD‐L1 in patients with advanced NSCLC in a large Latin American cohort. [ABSTRACT FROM AUTHOR]