Among post-menopausal women, we observed that the associations of LEP rs2167270 and rs4731426 with CRC varied according to history of estrogen-only (EO) hormone replacement therapy (HRT) use, categorically defined as 0 years (Never users), <10 years, and ≥10 years (pFDR for interaction: 0.02 and 0.02, respectively). This evidence concerns the gene LEP and colorectal carcinoma.