Background: Chronic inflammation is an important pathological factor in colorectal tumorigenesis. Lymphotoxin-alpha (LT-α), a pleiotropic pro-inflammatory cytokine has been shown to possess both cancer promoting and cancer inhibiting activities. Several studies have analyzed the association of intronic LT-α+252A/G single-nucleotide polymorphism (SNP) in human LT-α gene with various cancers including colorectal cancer (CRC), but the outcome have been mixed and inconclusive. Materials and Methods: The present case-control study analyzed the association of LT-α+252A/G SNP with CRC risk in the ethnic Kashmiri population. The genotype frequencies of LT-α+252A/G intronic SNP were compared between 142 CRC patients and 184 individually matched healthy controls by polymerase chain reaction-restriction fragment length polymorphism method. The association between the LT-α+252A/G SNP and CRC risk was investigated through conditional logistic regression models adjusted for multiple possible confounding (third) variables. Further, the association between CRC risk and various clinico-pathological parameters, demographic variables, and environmental factors within the case group subjects and the SNP under study was also analyzed. Results: The overall association between the LT-α+252A/G SNP and the modulation of CRC risk was found to be significant (P = 0.013). Further, we found a significant effect modification of the association between the LT-α+252A/G SNP genotypes and CRC risk by gender (P = 0.046). We also found that the LT-α+252A/G SNP within the case group was significantly associated with gender (P = 0.0014) and lymph node status (P