Abstract: Ospemifene (Ophena™) is a new selective oestrogen receptor modulator currently in phase III clinical development for treatment of post-menopausal vulvar and vaginal atrophy. In the present study, we examined the pharmacokinetics, toxicity, and DNA adduct forming potential of ospemifene in the liver and endometrium of rhesus macaques following single and subchronic dosing schedules to better understand the potential toxicologic effects of ospemifene. During single weekly dosing, six macaques were administered 35 mg/kg/week ospemifene orally for 3 weeks. Pharmacokinetics, haematologic toxicity, uterotrophic effects and serum cholesterol levels were monitored. Additionally, two animals were subchronically dosed with 60 mg ospemifene for 9 weeks, followed by 12 mg/day for 3 weeks. Serum cholesterol and pharmacokinetics were monitored, and serial liver and endometrial biopsies were collected during and after treatment to evaluate DNA adduct formation. Following single weekly dosing, no significant haematologic toxicities or uterotrophic effects associated with ospemifene were observed. Peak absorption was 4–5 hr, and the elimination half-life was approximately 22 hr. Serum low-density lipoprotein and triglyceride levels trended lower while no other effects on serum lipids were observed. Subchronic dosing resulted in no haematologic toxicity, a lowering of low-density lipoprotein and triglyceride levels, and an increase in high-density lipoprotein levels that were reversed following cessation of dosing. No clinically relevant uterine or endometrial effects were observed, and no DNA adducts were detected in the liver or endometrial biopsies. The results of our pilot study show that ospemifene may lack genotoxic and toxic effects while having a favourable pharmacokinetic profile.