Aims: To investigate whether vaginal estrogen cream combined with tolterodine is more effective than tolterodine alone in the treatment of postmenopausal women with overactive bladder (OAB). Materials and Methods: This is an unblinded study without placebo. A preliminary study consisted of tolterodine 2 mg twice per day for 3 months had been conducted for 25 postmenopausal women with OAB. Over a period of 11 months, 80 postmenopausal women with OAB underwent a prospective randomized trial. These patients were equally randomized into two groups. The interventions for the 12-week treatment period included 2 mg tolterodine twice per day for the group A and 2 mg tolterodine twice per day/vaginal conjugated equine estrogen 0.625 mg twice a week for the group B. Identical pre- and post-treatment assessments included bladder diary, Urogenital Distress Inventory-6 (UDI-6), and Incontinence Impact Questionnaire-7 (IIQ-7). Results: All 80 women (65.2 years, range 58-73) completed this study. The between groups comparison showed that the group B had significant improvements in mean daytime frequency and voided volume after treatment (14.8-5.8 vs. 14.1-6.4, P = 0.001 and 115.8-141.9 vs. 108.5-134.5, P = 0.007, respectively). Additionally, a comparison of the final total scores of UDI-6 and IIQ-7 between the two groups revealed that the group B had a statistically significant improvement in quality of life than that in the group A (8.6-6.9 vs. 9.5-7.2, P < 0.001 and 9.4-6.1 vs. 10.2-6.5, P < 0.001, respectively). Changes in the other symptoms, including nocturia, urgency and urge incontinence, were not statistically significant but actually achieved improved in both groups. Conclusions: A combination of vaginal estrogen cream and tolterodine is a potential therapy for postmenopausal women with OAB. © 2008 Wiley-Liss, Inc.