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To assess the efficacy of a preemptive antifungal therapy in preventing proven candidiasis in critically ill surgical patients.Before/after intervention study, with 2-yr prospective and 2-yr historical control cohorts.Surgical intensive care unit (SICU) in a university-affiliated hospital.Nine hundred and thirty-three patients, 478 in the prospective group and 455 in the control group, with SICU stay ≥5 days.During the prospective period, systematic mycological screening was performed on all patients admitted to the SICU, immediately at admittance and then weekly until discharge. A corrected colonization index was used to assess intensity of Candida mucosal colonization. Patients with corrected colonization index ≥0.4 received early preemptive antifungal therapy (fluconazole intravenously: loading dose 800 mg, then 400 mg/day for 2 wks).End points of this study were the frequency of proven candidiasis, especially SICU-acquired candidiasis. During the retrospective period, 32 patients of 455 (7%) presented with proven candidiasis: 22 (4.8%) were imported and 10 (2.2%) were SICU-acquired cases. During the prospective period, 96 patients with corrected colonization index ≥0.4 of 478 received preemptive antifungal treatment and only 18 cases (3.8%) of proven candidiasis were diagnosed; all were imported infections. Candida infections occurred more frequently in the control cohort (7% vs. 3.8%; p = .03). Incidence of SICU-acquired proven candidiasis significantly decreased from 2.2% to 0% (p < .001, Fisher test). Incidence of proven imported candidiasis remained unchanged (4.8% vs. 3.8%; p = .42). No emergence of azole-resistant Candida species (especially Candida glabrata, Candida krusei) was noted during the prospective period.Targeted preemptive strategy may efficiently prevent acquisition of proven candidiasis in SICU patients. Further studies are being performed to assess cost-effectiveness of this strategy and its impact on selection of azole-resistant Candida strains on a long-term basis.