ABSTRACT Background Post-menopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically-relevant, molecularly-defined tumor subtypes and tumor location. Methods We pooled data on tumor subtypes (microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8,220 post-menopausal women (3,898 cases and 4,322 controls) from eight observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of ever versus never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were two-sided. Results Among post-menopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR[95%CI]=0.62[0.56–0.69]). This association was similar according to MSI, CIMP, BRAF, or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (0.81[0.66–1.01]) compared with the adenoma-carcinoma pathway (0.63[0.55–0.73]; Phet=.04) and alternate pathway (0.61[0.51–0.72]). Additionally, proximal colon tumors had a weaker association (0.71[0.62–0.80]) compared with rectal (0.54[0.46–0.63]) and distal colon (0.57[0.49–0.66]; Phet=.01) tumors. Conclusions We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.