AbstractThe intra‐ and intertumoral heterogeneity of epithelial cells in human papillomavirus (HPV⁺) cervical adenocarcinoma (CEAD) remains largely unknown. To investigate this issue, we performed single‐cell RNA sequencing on 19 229 epithelial cells sorted from three tumor samples of three patients with HPV⁺ CEAD. Six epithelial subclusters (Epi1–Epi6) were identified that showed distinct gene expression. Among these, Epi1 and Epi4 had apparent tumor hallmarks and metabolic activities. Epi1 was highly enriched in hallmarks of hypoxia, IL2/STAT5 signaling, retinol metabolism, glycolysis, and arachidonic acid metabolism, while Epi4 was highly enriched in hallmarks of G2M checkpoint, E2F targets, DNA repair, PI3K/AKT/MTOR signaling, glycolysis, fatty acid degradation, TCA cycle, and glutathione metabolism. We also investigated intertumoral epithelial heterogeneity and found that Patient 1 was highly enriched for KRAS signaling and angiogenesis, while Patient 2 was highly enriched for epithelial–mesenchymal transition and TGF‐β signaling, and Patient 3 was highly enriched for hypoxia, DNA repair, G2M checkpoint, and E2F targets. Using single‐cell RNA sequencing, we revealed the intra‐ and intertumoral heterogeneity of epithelial cells in HPV⁺ CEAD, providing insights into the importance of personalized treatment for patients with HPV⁺ CEAD.