OBJECTIVE: To determine possible differences in the rate at which hormone replacement therapy (HRT) is continued among postmenopausal women treated initially with transdermal estradiol versus those treated initially with oral conjugated estrogens. DESIGN: A retrospective database search for prescription use. SETTING: Northern California facilities of Kaiser Permanente, a health maintenance organization. PATIENTS: Women aged > or = 45 years who filled index prescriptions for HRT during 1995 for either 0.05 mg transdermal estradiol semiweekly or 0.625 mg oral conjugated estrogen daily. All had filled prescriptions for medroxyprogesterone acetate (MPA) on the same day as the index estrogen prescription. RESULTS: We found statistically significantly greater relative risk (RR) of discontinuation among women whose HRT began with transdermal estradiol compared with women whose HRT began with oral conjugated estrogens [RR = 2.6, 95% confidence interval (CI) = 1.8-3.8]. After multiple adjustments, RR was 2.7 (95% CI = 1.8-3.9). Complete discontinuation of HRT treatment accounted for most of the stopping we observed, but more women switched from transdermal to oral (25% of those discontinuing this route) than switched from oral to transdermal (0.9% of those discontinuing this route). Risk of discontinuation was not associated with whether prescriber was a gynecologist (RR = 1.2, 95% CI = 0.9-1.7). Type of progestin schedule (cyclic vs. continuous combined) also was not a predictor for discontinuation (RR = 0.9, 95% CI = 0.8-1.0). Older age at start of treatment was associated with discontinuation (RR = 1.1, 95% CI = 1.0-1.2) for every additional 5 years of age. CONCLUSION: Among women starting HRT, those using a semiweekly transdermal estradiol regimen have a lower rate of continuation than do those using oral estrogen daily.