Combinations of posaconazole (POS) and tacrolimus (TCR) display enhanced activity over either drug alone in an immunosuppressed murine model of cutaneous mucormycosis (n = 10 mice per treatment group). Necrotic skin lesions were significantly reduced, as revealed by gross examination (A) and digital caliper measurement (B) in animals that received the POS 40 mg/kg plus TCR 1 mg/kg combination regimen daily versus controls or animals that received either drug alone. *P = .001 vs control; **P = .02 vs POS alone. C, Smaller lesion area was associated with reduced hyphal invasion of subcutaneous tissue and thigh muscle, by histologic analysis. Representative images of tissue collected from necrotic lesions and stained by Grocott–Gomori methenamine silver before imaging at an original magnification of 200×. Scale bar = 20 μm. D, Combination therapy resulted in a significantly lower tissue fungal burden, as reflected by analysis of chitin concentrations in tissue. Data are presented as mean values ± SD of glucosamine equivalents. *P < .05, by the Kruskal–Wallis test with Dunn's test.