<p>The nuclear receptor liver receptor homolog 1 (LRH1)/NR5A2 is aberrantly expressed in diverse cancer types, including liver and lung cancers. Since we previously showed that excessive phosphorylation of human LRH1 at S510 (hLRH1^pS510-high) is predictable of hepatocellular carcinoma recurrence, we here clarified the clinicopathological and biological significance of hLRH1^pS510-high in lung cancer. By immunohistochemistry using an anti-hLRH1^pS510 monoclonal antibody, we evaluated the hLRH1^pS510 signals in 151 and 150 cases of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues, respectively, and performed clinicopathological analysis. hLRH1^pS510 was localized in the nucleus of tumor cells in LUAD and LUSC tissues with different intensity and proportions among the patients. Of note, the strong hLRH1^pS510 signal was occasionally detectable in LUAD and LUSC cells at the expanding tumor edges. A semi-quantitative analysis revealed that 28 (18.4%) and 36 (24.0%) of LUAD and LUSC cases, respectively, exhibited hLRH1^pS510-high. Kaplan-Meier plots showed significant differences in the disease-free survival (DFS) between the hLRH1^pS510-high and hLRH1^pS510-low groups in LUSC, but not in LUAD patients. hLRH1^pS510-high was also significantly correlated with recurrence in LUSC patients. Additionally, by multivariate analysis, hLRH1^pS510-high represented an independent biomarker for the DFS of LUSC patients. Furthermore, the impact of hLRH1^pS510 on the viability of LUSC cells was evaluated by comparing phenotypes among two distinct LUSC cell lines expressing wild-type LRH1, LRH1S510A, and LRH1S510E. Consequently, we demonstrated that phosphorylation of hLRH1S510 accelerates the viability of LUSC cells. Thus, hLRH1^pS510 is attractive not only as the predictive biomarker for LUSC but also as the potential therapeutic target.</p>