We performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes. Integrative comparison of cHCC-ICC with hepatocellular carcinoma and intrahepatic cholangiocarcinoma revealed that combined and mixed type cHCC-ICCs are distinct subtypes with different clinical and molecular features. Integrating laser microdissection, cancer cell fraction analysis, and single nucleus sequencing, we revealed both mono- and multiclonal origins in the separate type cHCC-ICCs, whereas combined and mixed type cHCC-ICCs were all monoclonal origin. Notably, cHCC-ICCs showed significantly higher expression of Nestin, suggesting Nestin may serve as a biomarker for diagnosing cHCC-ICC. Our results provide important biological and clinical insights into cHCC-ICC. Display omitted •We build the genomic and transcriptomic landscape of 133 cHCC-ICCs•Integrative genomic analysis reveals distinct cHCC-ICC subtypes•Both mono- and multiclonal origins of cHCC-ICC are identified•Nestin expression can serve as a biomarker for the diagnosis and prognosis of cHCC-ICC Xue et al. perform genomic and transcriptomic analyses of combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC). They show that combined and mixed types of cHCC-ICC have different clinical and molecular features and that Nestin expression may be a diagnostic biomarker for cHCC-ICC.