BackgroundLeukocyte telomere length (LTL) is related to prostate cancer (PCa). However, the causal relationship between them remains unknown. This study was aimed at identifying the causal direction between LTL and PCa with Mendelian randomization (MR).MethodsSingle-nucleotide polymorphisms associated with LTL were identified from a genome-wide association study (GWAS) involving 472,174 individuals. Summary-level data of PCa-related GWAS were extracted from four cohorts comprising 456,717 individuals. An inverse-variance-weighted (IVW) algorithm was used for MR. Sensitivity analyses were performed with MR-Egger regression, IVW regression, leave-one-out test, and MR-Pleiotropy Residual Sum and Outlier analyses. A meta-analysis was also performed to compute the average genetically determined effect of LTL on PCa.ResultsA long LTL was associated with an increased risk of PCa in all cohorts, with odds ratios of 1.368 (95% confidence interval [CI]: 1.247 to 1.500,P= 2.84×10−11), 1.503 (95% CI: 1.243 to 1.816,P= 2.57×10−5), 1.722 (95% CI: 1.427 to 2.077,P= 1.48×10−8), and 1.358 (95% CI: 1.242 to 1.484,P= 1.73×10−11) in the IVW analysis. Sensitivity analyses showed that the genetically determined effect of LTL on PCa was stable and reliable. The meta-analysis showed that the genetically determined per 1-standard deviation rise in LTL correlated significantly with an average 40.6% increase in the PCa risk, with an average odds ratio of 1.406 (95% CI: 1.327 to 1.489,P< 0.001).ConclusionThe results of this study supported the causal hypothesis that the genetically determined longer LTL was associated with a higher risk of PCa. This finding could serve as a basis for therapeutic strategies for PCa.