Background: Gynecologic symptoms and sexual dysfunction from endocrine therapy are troublesome side effects for a significant number of patients. This study explored amelioration of vaginal dryness and dyspareunia with fluocinonide cream, a strong topical corticosteroid. Methods: A single-arm, open-label phase II trial of topical fluocinonide 0.05% cream to improve vaginal symptoms in women on endocrine therapy in the adjuvant setting for early stage breast cancer was performed. Patients with vaginal symptoms applied topical vaginal fluocinonide 0.05% cream twice a day for two weeks then once daily for two weeks. Patients were assessed for symptoms by weekly completion of the Mayo/North Central Cancer Treatment Group Patient Pretreatment Questionnaire. The primary outcome was a change from baseline in patient-reported effects of vaginal dryness and dyspareunia on a scale from 0 (no symptoms) to 4 (very severe symptoms) from time of enrollment and at 4 weeks. Secondary outcomes were decrease in vaginal itching and total vaginal index score. Comparisons were made with Wilcoxon sign rank test with 2.5% significance level. Results: Thirty-four women were accrued. At 4 weeks compared with baseline, vaginal dryness improved from a median score of 2 (moderate symptoms) to 0 (no symptoms) (P < .001) and dyspareunia from 3 (severe symptoms) compared with 1 (mild symptoms) (P = .002). Percentage of patients who had > 2 point improvement in vaginal dryness and dyspareunia was 69.0% and 75% respectively. Secondary analysis showed decrease in vaginal itching score from 1 to 0 (P = .001) and vaginal index score of 6 to 1 (P = .002). Twenty-one patients experienced low-grade toxicities which were mostly limited to skin irritation. Conclusions: Fluocinonide 0.05% cream improves vaginal dryness and dyspareunia experienced by women receiving endocrine therapy and has the potential to improve quality of life of cancer survivors and compliance of endocrine therapy. Clinical trial information: NCT00297011