Objective To investigate the expression levels of HHLA2 and the transcription factor FOXO3A in non-small cell lung cancer(NSCLC)tissues and their relationship with clinical prognosis.Methods A total of 147 NSCLC patients who re-ceived examination and treatment were selected as the study subjects.The expression of HHLA2 and FOXO3A in cancer tissues and adjacent non-cancerous tissues was measured using immunohistochemistry.Multivariate Cox regression analysis was used to i-dentify factors related to the prognosis of NSCLC patients.Results HHLA2 was highly expressed in NSCLC tissues(57.1%vs.42.9%),while the positive rate of FOXO3A protein was lower than that in adjacent tissues(34.7%vs.65.3%)(P<0.05).HHLA2 protein was significantly associated with TNM stage,lymph node status,and recurrence,while FOXO3A was only associat-ed with TNM stage and lymph node status.Univariate regression analysis confirmed that TNM stage Ⅲ~Ⅳ,lymph node metasta-sis,recurrence,HHLA2 positive and FOXO3A negative were correlated with 5-year survival of patients;Multivariate regression a-nalysis showed that TNM stage Ⅲ~Ⅳ,lymph node metastasis,HHLA2 positive and FOXO3A negative were independent risk fac-tors affecting the prognosis of NSCLC patients.NSCLC patients who were HHLA2-negative and FOXO3A-positive had a signifi-cantly higher 5-year overall survival rate compared to HHLA2-positive and FOXO3A-negative patients(P<0.05).Conclusion Increased expression of HHLA2 and decreased expression of FOXO3A in NSCLC tissues may be independent risk factors affecting the prognosis of NSCLC patients.