Objective:Leptin (LEP) is an obesity-associated adipokine associated with tumor cell growth. We examined the relevance of genetic variants ofLEPand leptin receptor (LEPR) to colorectal cancer (CRC) survival by using data from the Newfoundland Familial Colorectal Cancer Study.Methods:A total of 532 patients newly diagnosed with CRC between 1997 and 2003 were followed up until April 2010. Data on their demographics and lifestyles were collectedviaquestionnaires. Genotyping of blood samples was performed with the Illumina Human Omni-Quad Bead chip. Multivariable Cox models were used to assess the relationships of 35 tag single-nucleotide polymorphisms (SNPs) inLEPandLEPRwith overall survival (OS), disease-free survival (DFS), and CRC-specific survival.Results:At the gene level,LEPwas associated with DFS (P= 0.017), andLEPRwas associated with both DFS (P= 0.021) and CRC-specific survival (P= 0.013) in patients with CRC. In single-SNP analysis,LEPrs11763517,LEPRrs9436301, andLEPRrs7602 were associated with DFS after adjustment for multiple testing. TheLEPRhaplotypes G-C-T (rs7534511-rs9436301-rs1887285) and A-A-G (rs7602-rs970467-rs9436748) were associated with prolonged OS among patients with CRC overall (G-C-T: HR, 0.63; 95% CI, 0.43–0.93; A-A-G: HR, 0.59; 95% CI, 0.38–0.91) and those diagnosed with colon cancer (G-C-T: HR, 0.54; 95% CI, 0.34–0.86; A-A-G: HR, 0.49; 95% CI, 0.29–0.83). Similar results were observed for DFS. Moreover, significant interactions were found amongLEPRrs7602 (Avs.G),LEPRrs1171278 (Tvs. C), red meat intake, and BMI status: the associations between these variants and prolonged DFS were limited to patients with below-median red meat consumption and body mass index (BMI) < 25 kg/m2.Conclusions:Polymorphic variations in theLEPandLEPRgenes were associated with survival of patients after CRC diagnosis. TheLEP/LEPR-CRC survival association was modified by participants’ red meat intake and BMI.