Background: LCNEC and SCLC are aggressive neuroendocrine carcinomas with overlap in clinical, histopathologic, morphologic and genomic features. Differential molecular features between the two subtypes have not been well elucidated, contributing the uncertainty for optimal clinical strategy for each subtype. Here we interrogated the genomic characteristics in LCNEC as compared to SCLC along with their histologically related subtypes: carcinoids and atypical carcinoids via comprehensive genomic profiling. Methods: FFPE samples from 31 LCNECs, 35 SCLCs, 14 carcinoids and 22 atypical carcinoids were sequenced in a CLIA-certified sequencing laboratory using 520-cancer-related gene panel, with an average sequencing depth of 1385×. Results: Comparative mutational analysis revealed that both LCNEC and SCLC sub-cohorts displayed higher rate of TP53 alterations than that of carcinoid (p < 0.001, p < 0.001). SCLC patients harbored more RB1 and PIK3CA mutations than LCNECs (p < 0.001, p = 0.014) and carcinoids (p < 0.001, p = 0.018). In addition, mutation frequencies of LRP1B, FAT1, PRKDC, NOTCH1, SPTA1, EPHA3 and KEAP1 in SCLC were significantly higher than that in carcinoid. Mutations in TP53 and RB1 occurred concurrently in 83% (29/35) SCLC patients, whereas in only 32.3% (10/31) LCNECs. We further investigated the distribution of mutations across KEGG pathways and found that mutation frequencies in both HIF-1 and Notch signaling pathways were lower in LCNEC than SCLC (p = 0.032, p = 0.025). Copy number variation (CNV) analysis revealed that LCNEC and SCLC had comparable CNVs which were significantly higher than carcinoid (p < 0.001, p < 0.001) and atypical carcinoid (p = 0.010, p = 0.028). TMB analysis also revealed a comparable TMB status of LCNEC (12.7/Mb) and SCLC (11.9/Mb), and relatively lower TMB in both carcinoid (2.4/Mb, p < 0.001, p < 0.001) and atypical carcinoid (5.6/Mb, p = 0.003, p = 0.009) than LCNEC and SCLC. Conclusions: We demonstrated the differential genomic characteristics in the four subtypes of neuroendocrine carcinomas. Compared with SCLC, LCNEC has lower mutation frequencies in RB1, PIK3CA, as well as HIF-1 and Notch signaling pathways. In addition, LCNEC and SCLC had comparable CNV and TMB status, which significantly higher than that of carcinoids and atypical carcinoid.