Aims: Miconazole is a synthetic imidazole antifungal that has a broad spectrum of activity against Candida albicans and non-albicans Candida species. The aim of this study was to evaluate the efficacy and safety of miconazole nitrate vaginal suppository and oral fluconazole in treating severe vulvovaginal candidiasis (SVVC). Methods: In this prospective, randomized case control study, 577 cases of consecutive patients with SVVC were studied at the Gynecological Clinic of Peking University Shenzhen Hospital from January 1, 2009 through December 31, 2010. Patients with SVVC were treated with two doses of miconazole nitrate vaginal suppository 1,200 mg or two doses of fluconazole 150 mg. The patients were followed up for 7-14 and 30-35 days following the second dose of therapy. Results: The mycological cure rates of the patients on days 7-14 of follow-up were 75.9% (220/290) and 84.0% (241/287) in the miconazole and fluconazole groups, respectively (p < 0.05). The mycological cure rates of the patients at the second follow-up were 64.8% (188/290) and 69.7% (200/287), respectively, in the two groups (p > 0.05). Conclusion: The study demonstrated that two doses of miconazole nitrate vaginal suppository 1,200 mg were as effective as two doses of an oral fluconazole 150 mg regimen in the treatment of patients with SVVC.