Contemporary data from randomized clinical trials focusing on the effect of oral hormone therapy (HT) on venous thromboembolism (VTE) in women aged 50–60 years are scarce despite evolving HT regimens. Here, we evaluated the association between HT and the risk of developing VTE using a target trial emulation among women of menopausal age. This retrospective cohort study applied a target trial emulation framework using claims data from a universal health insurance program in Taiwan. We emulated a sequence of trials in which women aged 50–60 years with no previous history of HT, hysterectomy, gynecologic disorders, or cardiovascular events were enrolled. Eligibility and HT use were evaluated monthly from 2011 to 2019. Eligible women were classified as either HT initiators or non-initiators for each consecutive month. Observational analogs of the intention-to-treat and per-protocol effects were estimated using pooled logistic regression models. Of the 150,686,148 eligible person-trials (3,001,112 women), 192,215 initiators and 768,860 propensity score-matched non-initiators were included in the analysis. The average duration of the HT was 1.25 years. Over a median follow-up of 5.83 years, 3,334 women developed VTE. The estimated hazard ratio (95% confidence interval) was 0.96 (0.88, 1.04) in the intention-to-treat analysis and 0.66 (0.41, 1.05) in per-protocol analysis. The estimated intention-to-treat and per-protocol 5-year VTE-free survival differences (95% confidence interval) were 0.1‰ (− 0.3‰, 0.7‰) and 0.3‰ (− 2.8‰, 4.0‰), respectively. In the contemporary clinical setting, we did not observe an increased VTE risk associated with HT in women aged 50–60 years.