Cellular diversity in tumors is a key factor for therapeutic failures and lethal outcomes of solid malignancies. Here, we determined the single-cell transcriptomic landscape of liver cancer biospecimens from 19 patients. We found varying degrees of heterogeneity in malignant cells within and between tumors and diverse landscapes of tumor microenvironment (TME). Strikingly, tumors with higher transcriptomic diversity were associated with patient's worse overall survival. We found a link between hypoxia-dependent vascular endothelial growth factor expression in tumor diversity and TME polarization. Moreover, T cells from higher heterogeneous tumors showed lower cytolytic activities. Consistent results were found using bulk genomic and transcriptomic profiles of 765 liver tumors. Our results offer insight into the diverse ecosystem of liver cancer and its impact on patient prognosis. Display omitted •HCC and iCCA have a varying degree of transcriptomic diversity•Tumor transcriptomic diversity is associated with patient outcomes•Tumor-derived VEGF drives microenvironmental reprogramming•T cells derived from higher heterogeneous tumors showed lower cytolytic activities Ma et al. perform single-cell RNA sequencing of primary liver cancers and find heterogeneity in malignant cells and in the tumor microenvironment, the degree of which negatively associates with patient prognosis. They demonstrate that VEGF expression is linked to tumor diversity and T cell dysfunction.