The effects of both progesterone- and norethisterone-loaded intravaginal rings were investigated in twenty-five rhesus monkeys for 52 weeks. The intravaginal rings were designed to provide a sustained release of either the human dosage level of the hormone or ten times this level. Untreated placebo rings were used for control purposes. The devices were well retained. With the exception of increased plasma fibrinogen levels in animals treated with norethisterone, no marked differences in either local or systemic toxicity between the progesterone and norethisterone intravaginal rings were apparent. Following insertion of the hormone-treated intravaginal rings, a dose-related decrease in vaginal bleeding was recorded. The vaginal microbial flora were assessed qualitatively and semiquantitatively and all groups including the placebo controls showed a changes in mcirobial populations. Terminal studies indicated that at high dose levels, ovulation was suppressed and widespread atrophy of the uterine mucosal and glandular endometrial epithelium had occurred. An increase in cervical mucus was observed within the lumen of the endocervical canal in a proportion of hormone-treated animals. In the vagina, a dose-related focal or diffuse atrophy of the mucosal epithelium was found.