A large cohort analysis linked tirzepatide use to lower short-term endometrial cancer diagnosis risk compared with lifestyle modification. In a retrospective study of more than 350,000 women with overweight or obesity, tirzepatide users showed a reduced hazard of newly recorded endometrial cancer diagnoses over two years. The findings extend the ongoing post-approval evidence base around incretin-based therapies and cancer risk, but they also highlight the observational nature of the evidence: confounding and detection effects remain potential limitations inherent to retrospective registry studies. Still, the signal is clinically salient given the large treated population and the seriousness of endometrial cancer. Further confirmation with prospective designs or robust causal methods will be needed before the result can inform risk counseling beyond existing guidance.