BackgroundLifelong premature ejaculation (LPE) is one of the most common ejaculatory dysfunctions in men. The serotonin (5-HT) synthesis rate-limiting enzyme (TPH2) and receptor (HTR1A) in the 5-HT regulatory system may play a key role in the pathogenesis of LPE. However, there are few studies on the effects ofTPH2andHTR1Apolymorphisms on LPE risk. We speculated thatTPH2andHTR1Apolymorphisms may affect the occurrence and development of LPE in the Chinese Han population.MethodsIn this study, 91 patients with LPE and 362 normal controls aged 18 to 64 years were enrolled in the male urology department of Hainan General Hospital in China from January 2016 to December 2018. The SNPs inHTR1AandTPH2, which are related to 5-HT regulation, were selected as indexes to genotype the collected blood samples of participants. Logistic regression was used to analyze the correlation between SNPs ofHTR1AandTPH2with LPE susceptibility, as well as the relationship with leptin, 5-HT and folic acid levels.ResultsThe results revealed thatHTR1A-rs6295 increased LPE risk in recessive model. Rs11178996 inTPH2significantly reduced susceptibility to LPE in allelic (odds ratio (OR) = 0.68, 95% confidence interval (95% CI) = 0.49–0.96,p= 0.027), codominant (OR = 0.58, 95% CI = 0.35–0.98,p= 0.040), dominant (OR = 0.58, 95% CI = 0.36–0.92,p= 0.020), and additive (OR = 0.71, 95% CI = 0.52–0.98,p= 0.039) models. Grs11179041Trs10879352could reduce the risk of LPE (OR = 0.44, 95% CI = 0.22–0.90,p= 0.024) by haplotype analysis.ConclusionHTR1A-rs6295 andTPH2-rs11178996 are associated with LPE risk in the Chinese Han population based on the finding of this study.