Introduction <p>Current guidelines recommend fluconazole as first-line therapy for pulmonary cryptococcosis. However, clinical reports indicate that fluconazole treatment fails in some patients. Voriconazole is frequently used in these cases, yet its effectiveness has not been comprehensively studied or validated.</p> Method <p>This multicenter real-world retrospective study enrolled patients with fluconazole treatment failure who were divided into two groups based on subsequent antifungal therapy: continuation of fluconazole or switch to voriconazole. Overall treatment responses were evaluated at predetermined endpoints for both groups, with safety outcomes also assessed.</p> Result <p>Initial fluconazole treatment achieved success in 82.72% of patients. Among patients with fluconazole treatment failure, 19 were assigned to the control group (continued fluconazole) and 15 to the voriconazole group. At day 60, the voriconazole group demonstrated a significantly higher response rate compared to the fluconazole group (66.67% [<i>n</i> = 10] vs. 15.79% [<i>n</i> = 3], <i>p</i> = 0.002). However, at day 180, response rates were comparable between groups (66.67% [<i>n</i> = 10] vs. 68.42% [<i>n</i> = 13], <i>p</i> = 0.914). The incidence of adverse reactions did not differ significantly between groups (20.00% [<i>n</i> = 3] vs. 15.79% [<i>n</i> = 3], <i>p</i> = 0.439).</p> Conclusion <p>The majority of patients achieved favorable therapeutic outcomes with initial fluconazole treatment. In patients experiencing fluconazole treatment failure, switching to voriconazole demonstrated superior short-term efficacy compared to continued fluconazole therapy; however, long-term outcomes were comparable between the two treatment approaches.</p>