Objective: To evaluate the efficacy and safety of high-dose fluconazole alone or combined with flucytosine as initial therapy for cryptococcal meningitis (CM) in non-human immunodeficiency virus (HIV)-related patients. Methods: Twenty-five non-HIV-infected patients with CM from June 2015 to September 2018 in Huashan Hospital, Fudan University, who were initially treated with high-dose fluconazole with or without flucytosine for at least seven days were retrospectively reviewed.Clinical features and antifungal (600-800 mg/d) regimens were recorded, clinical responses and drug-related adverse events were evaluated. Mann-Whitney test and Fisher′s exact probabilities test were applied to compare variables between groups. Results: Of the 25 patients enrolled in this study, 15 had predisposing factors. Headache (25 cases), fever (21 cases), vomiting (13 cases) and neck stiffness (13 cases) were common manifestations. Abnormalities of cranial computed tomography (CT) scan and/or magnetic resonance imaging (MRI) were found in 22 cases.Nineteen patients were treated with high-dose fluconazole plus flucytosine for initial therapy, and six patients were treated with high-dose fluconazole alone. The course of initial regimens with high-dose fluconazole was 42 (29, 120) days. At the end of initial therapy, partial response in 20 patients, stable response in three patients and death in two patients were observed, and the overall effective rate was 80%(20/25). In treatment failure group of initial treatment, the proportion of patients with baseline cerebrospinal fluid opening pressure over 300 mmH₂O (1 mmH₂O=0.009 8 kPa) and with altered mental status were both significantly higher compared with those in treatment success group. Fluconazole related adverse drug events were observed including elevated transaminases (one case), gastrointestinal symptoms combined with hypokalemia (two cases), and systemic rash (three cases). Except for three patients with rash reduced the dosage of fluconazole, no other patients were given dosage adjustment. Conclusion High-dose fluconazole alone or combined with flucytosine is effective and safe for the initial therapy of non-HIV-related CM patients.