A pilot study was performed comparing the efficacy and safety of continuous versus sequential schedules of the two most commonly prescribed medications for ovarian hormone replacement, conjugated equine estrogens and medroxyprogesterone acetate. Bleeding patterns, endometrial histology, and metabolic parameters were studied in 48 postmenopausal women prospectively randomized to a continuous schedule (daily estrogen and progestin) or a sequential schedule (conjugated estrogen on days 1-25, medroxyprogesterone acetate on days 16-25). Doses studied were 0.625 and 1.25 mg of conjugated estrogens and 10 mg of medroxyprogesterone acetate. Significantly greater bleeding was observed with the 1.25-mg dosage of conjugated estrogens. Bleeding patterns were similar between schedules, with the exception that amenorrhea was more prevalent in the women using the 1.25-mg dosage of estrogen and the continuous progestin schedule. More frequent endometrial atrophy was observed with the continuous schedule, supporting the concept that prolonged use of this schedule may promote amenorrhea in most patients. Both doses and schedules were associated with modest and insignificant increases in high-density lipoprotein cholesterol. Sequential therapy did not prevent the estrogen-induced decrease of low-density lipoprotein cholesterol, whereas the continuous schedule did, particularly with 0.625-mg dosage of conjugated estrogens. Significant increases of triglycerides were also seen with the continuous but not with the sequential schedule. Because of reports that the continuous schedule using the 2.5-mg dosage of medroxyprogesterone acetate does not elicit these actions on circulating lipids, attention should be directed toward examining the long-term effects of this lower dosage given continuously.