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.