Objective: To identify the risk factors associated with invasive fungal infections (IFI) in immunocompromised patients (IP), and monitor antifungal therapy appropriateness and costs. Materials and Methods: The 1-year observational retrospective study was performed on 101 IP, who received antifungal intravenous therapy with fluconazole (F), liposomal amphotericin-B (A), caspofungin (C), itraconazole (I) for ≥4 days. Patient therapy was divided into three groups: Prophylactic, empirical, and target. Immunosuppressive therapy (IT), total parenteral nutrition (TPN), dialysis, central line, steroid therapy, stent use, neutropenia, and mechanical ventilation were evaluated. Variables were therapy duration, defined daily dose (DDD) consumption, DDD average cost. Results: Main risk factors were central line (65.3%), TPN (56.4%), dialysis (46.5%), IT (42.6%), mechanical ventilation (32.7%), neutropenia (24.8%), steroid therapy (23.8%), and stent use (14.9%). Average duration of prophylaxis was 7 days; F (61%), A (26%), and C (13%) were used. Average duration of empirical therapy was 8 days; F (52.9%), A (26.5%), C (8.8%), I (2.9%), and in association A + C, A + F, C + F (8.9%) were used. Average duration of target therapy was 9 days; F (40.4%), A (23.1%), C (15.4%), I (7.7%), and in association A + C, A + F, C + F (13.4%) were used. DDD consumption and DDD average-cost were: C 50 mg vial: 273 DDD, €381.1; C 70 mg vial: 33.6 DDD, €389.6; F 200 mg vial: 768 DDD, €11.8; F 100 mg vial: 89 DDD, €10.6; I 250 mg vials: 62.5 DDD, €68.8; and A 50 mg vial: 2200 DDD, €93.4; respectively. Conclusions: Data showed an appropriate use of antifungals. Best alternative therapy (cheaper antifungal drug) was prescribed for most patients. The high cost of A and C was justified by IFI resolution.