Background: Tumor cells expressing programmed cell death 1 ligand (PD-L1) are believed to suppress immune responses through activation of the PD-1/PD-L1 pathway. Recent data indicate that PD-L1 tumor status might be predictive for responses to PD-1- and PD-L1- directed therapies. Methods: PD-L1 expression was evaluated in genomically annotated 259 adenocarcinomas (AD) and 180 squamous cell carcinomas of the lung (SQ) using immunohistochemistry (IHC). Moreover, PD-L1 expression and its correlation with clinical data, histology and genotype were analyzed. Results: Tumors were considered PD-L1 positive if tumor cells showed at least weak membranous staining by IHC. 83 of 259 patients (pts.) with AD were positive for PD-L1 surface expression (=32,0%). The observed staining intensity was weak, intermediate and strong in 38, 33 and 12 cases respectively. 55 of 180 pts. with SQ were PD-L1⁺(=30,6%). The observed staining intensity was weak, intermediate and strong in 27, 21 and 7 cases respectively. For AD and SQ no significant association between PD-L1 expression and clinical characteristics (gender, smoking history, stage) could be found. PD-L1 expression in AD or SQ was not significantly associated with ALK translocation (n=178; n=138), BRAF mutation (mut.) (n=113; n=98), DDR2 mut. (n=59; n=64), EGFR mut. (n=124; n=101), FGFR2 mut. (n= 117; n=91), HRAS mut. (n=94; n=73), KRAS mut. (SQ, n=101), NFE2L2_exon2 mut. (AD, n=97), NRAS mut. (n=109; n=81), PIK3CA mut. (n=121; n=99), STK11 mut. (SQ, n=101), TP53 mut. (n=124; n=101) or RB1 deletion (SQ, n=109). However, PD-L1 expression in AD is significantly more frequent in KRAS mutated than in KRAS wild-type samples (n=126; p=0,002) and significantly more frequent in samples with deletion of RB1 (n=143; p=0,024). On the contrary, PD-L1 expression in AD is significantly less frequent in samples with STK11 mutations (n=122; p=0,022). Finally, PD-L1 expression in SQ is significantly more frequent in samples with a mutation in exon 2 of NFE2L2 (n=88; p=0,025). Conclusions: PD-L1 expression in the two most common histological NSCLC subtypes is associated with distinct genotypes that might further facilitate identification of pts. most suitable for therapeutic anti PD-1 and anti PD-L1 intervention.