OBJECTIVE: To determine possible differences in continuation of postmenopausal estrogen replacement therapy among women initiating treatment with transdermal estradiol versus those initiating treatment with oral estrogen. STUDY DESIGN: A retrospective database search. PATIENTS AND METHODS: We analyzed estrogen use among 45- to 74-year-old women who filled index prescriptions for estrogen during 1996 for either once-a-week transdermal estradiol or daily oral estrogen. Prescription use was analyzed separately for each of 2 groups: 276 hysterectomized women who filled prescriptions for estrogen alone (ERT) and 4182 women who filled prescriptions for medroxyprogesterone acetate (MPA) with estrogen (HRT) on the same day. RESULTS: Risk of discontinuing therapy after 12 months ranged from 59% to 76% among the 4 subgroups: ERT with unopposed transdermal estradiol; ERT with unopposed oral estrogen; HRT with MPA-opposed transdermal estradiol; and HRT with MPA-opposed oral estrogen. The relative risk (RR) of discontinuation was significantly greater among women starting HRT with transdermal estradiol than among women starting oral estrogen (RR = 1.5; 95% confidence interval [CI] = 1.3 to 1.8). RR of discontinuation among women starting ERT with transdermal estradiol compared with women starting oral estrogen therapy was 1.3 (95% CI = 1.0 to 1.8). CONCLUSIONS: Approximately 2 of 3 women who start either ERT or HRT discontinue therapy within a year, regardless of hysterectomy status. Furthermore, women who start ERT or HRT with a transdermal estradiol system are more likely to discontinue therapy.