Background: Large-cell neuroendocrine carcinoma (LCNEC) is a rare type of lung cancer with a poor prognosis. Due to its rarity, molecular characterization of LCNEC is not well elucidated. We aim to understand the genomic and immunologic landscape of LCNEC to identify molecular alterations and relevant biological pathways with potential therapeutic value. Methods: Comprehensive profiling including whole exome sequencing (WES), next-generation sequencing (NGS), whole transcriptome sequencing (WTS), and immunohistochemistry (IHC) for PD-L1 was performed (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations. LCNEC was categorized as small cell lung cancer (SCLC)-like LCNEC (TP53/RB1 co-mutated) and non-small-cell lung cancer (NSCLC)-like LCNEC (wild type for one or both of TP53/RB1). Molecular features of LCNEC were compared among the subgroups and with those of SCLC using the χ² test with Benjamini & Hochberg correction. Results: A total of 467 cases of LCNEC were included. Commonly altered genes (≥ 5%) included TP53 (79.1%), RB1 (36.8%), SMARCA4 (10.4%), ARID1A (10.3%), KRAS (9.7%), KEAP1 (9.2%), KMT2D (8.7%), STK11 (8.4%), NF1 (7.1%), PTEN (6.1%), and CDKN2A (5.9%). The prevalence of potentially actionable mutations was as follows: EGFR exon 19 deletion (0.48%), EGFR L858R (0.48%), ALK fusion (1.7%), KRAS G12C (2.9%). EGFR exon 19 deletion, EGFR L858R, and ALK fusion were exclusive to NSCLC-like LCNEC tumors. RET fusion, NTRK fusion and BRAF^V600E were not detected. Copy number alterations (CNAs) were found in MYC (8.8%), ZNF703 (4.1%), FOXA1 (4.0%), FGFR1 (4.0%), ATK2 (3.9%), CCNE1 (3.7%), FGF19 (3.4%), TNFRSF14 (3.4%), and CCND1 (2.7%). Over-expression of cMET was noted in 10% and PD-L1 expression (by 22C3 pharmDx) of > 1% was noted in 21.5% of samples. WTS detected cMET exon 14 skipping mutations in 2.4% of samples. High tumor mutation burden (TMB; ≥ 10 Mut/MB) was seen in 40.6%. Among the 467 cases of LCNEC, 112 (24%) were SCLC-like LCNEC and 335 (76%) NSCLC-like LCNEC. Mutations in KRAS (12%), STK11 (11%), CDKN2A (9%), and SMARCA4 (14%) were more common in NSCLC-like LCNEC, compared with SCLC-like LCNEC (p value < 0.05). 442 cases of SCLC were compared with LCNEC tumors. SLFN11:SLFN12 fusion events, detected by WTS, were exclusively seen in SCLC and were not seen in any of the LCNEC cases. Gene expression profiles revealed that 1) B cell infiltration was higher in SCLC-like LCNEC, compared with SCLC, and 2) NK and T cell infiltration was lower, but B-cell infiltration was higher in NSCLC-like LCNEC, compared with SCLC. Conclusions: LCNEC displays a broad pattern of genomic alterations that overlap in the SCLC-like subset with the classic alterations in SCLC. The distinct genomic alterations and transcriptomic profiles present opportunities for therapeutic targeting and inform a future framework for development of therapeutics for LCNEC.