OBJECTIVE: The purpose of this study was to examine the risk of first-ever stroke in relation to use of hormone replacement therapy (HRT) among middle-aged and older Swedish women. MATERIALS: A total of 16,906 women, 45-73 years old, from the 'Diet and Cancer' study in Malmö, Sweden were examined. Women were considered as HRT users if they took systemic hormone therapy regularly. Incidence of stroke was followed for a mean period of 10.5 years. RESULTS: In all, 2148 (12.7%) women used HRT. A total of 461 stroke cases occurred during follow-up, 48 of them in HRT users. Incidence of total stroke and ischemic subtype had no significant relation to HRT use. However, an increased risk of hemorrhagic stroke was found in women taking unopposed estrogen (RR=2.55, 95%CI: 1.03-6.35) or un-native estrogen regimens (RR=4.27, 95%CI: 1.71-10.66). Although not significantly, the risk of stroke was 33% lower in women who started their treatment before menopause. Among HRT users, the risk of stroke was associated with advancing age, smoking, excess body weight and hypertension. CONCLUSIONS: There is no significant association between hormone therapy and risk of total stroke in women during 10.5 years follow-up. Preparations of estrogen and time for initiation of treatment may affect the risk of stroke.