OBJECTIVE: To investigate the correlation between the expression of PD-L1 and HIF-1 alpha in hepatocellular carcinoma (HCC) tissue and further analyze the association with clinical parameters and the prognostic value of coexpression in HCC patients. METHODS: We assessed the expression of PD-L1 and HIF-1 alpha by immunohistochemistry in tumor tissue from 90 HCC patients who underwent curative hepatectomy. The results were validated in an independent cohort of additional 90 HCC patients. RESULTS: PD-L1 and HIF-1 alpha exhibited in tumor tissue high expression rates of 41.11% (37/90) and 43.33% (43/90), respectively, and their expressions were positively correlated (r = 0.563, P < .01). High expression of PD-L1 was significantly associated with low albumin levels (P < .05); high expression of HIF-1 alpha was significantly correlated with high alpha-fetoprotein (AFP) levels and low albumin levels (P < .05); high expression of both PD-L1 and HIF-1 alpha was also significantly associated with high AFP levels and low albumin levels (P < .05). High expression of PD-L1, HIF-1 alpha, as well as both PD-L1 and HIF-1 alpha was respectively significantly associated with worse overall survival (OS) and disease-free survival (DFS) (P < .05). Patients with co-overexpression of PD-L1 and HIF-1 alpha had the worst prognosis compared with other groups. Additionally, multivariate Cox regression models suggested that high expression of PD-L1, HIF-1 alpha, as well as both PD-L1 and HIF-1 alpha was an independent prognostic factor for OS and DFS (P < .05). Furthermore, the positive correlation and prognostic values of PD-L1 and HIF-1a were validated in an independent data set. CONCLUSION: We demonstrated that HCC patients with co-overexpression of PD-L1 and HIF-1 alpha in tumor tissue had a significantly higher risk of recurrence or metastasis and death compared with others. Therefore, more frequent follow-up is needed for patients with co-overexpression of PD-L1 and HIF-1 alpha. At the same time, a combinational therapy with HIF-1 alpha inhibitors in conjunction with PD-L1 blockade may be beneficial for HCC patients with co-overexpression in the future.