BACKGROUND: Fungal infections of inflatable penile prostheses (IPPs) are inadequately understood in the literature. AIM: To review a multi-institution database of IPP infections to examine for common patient and surgical factors related to IPP fungal infections. METHODS: This is a retrospective Institutional Review Board-approved analysis of 217 patients at 26 institutions who underwent salvage or device explant between 2001 and 2018. Patient data were compiled after an extensive record review. OUTCOMES: 26 patients (12%) with fungal infections were identified. RESULTS: 23 of 26 patients (83%) with a fungal IPP infection were either diabetic or overweight. 15 patients had undergone primary IPP implantation, and the other 11 had previously undergone an average of 1.7 IPP-related surgeries (range 1-3; median 2). The average age at implantation was 63 years (range 31-92; median 63). 18 of the 26 patients with fungal infection had diabetes (69%), with a mean hemoglobin A1c (HbA1c) value of 8.4 (range 5.8-13.3; median 7.5). Twenty-two patients (85%) were overweight or obese. The mean body mass index for all patients was 30.1 kg/m2 (range 23.7-45 kg/m2; median 28.4 kg/m2), and that for diabetic patients was 30.8 kg/m2 (range 24.1-45 kg/m2, median 29.7 kg/m2). Ninety-one percent of implants were placed with intravenous antibiotics, consistent with current American Urological Association guidelines: an aminoglycoside plus first- or second-generation cephalosporin or vancomycin or ampicillin/sulbactam or piperacillin/tazobactam. 65% (17 of 26) of infected IPPs had only fungal growth in culture. No patient had concomitant immunosuppressive disease or recent antibiotic exposure before IPP implantation. CLINICAL IMPLICATIONS: More than two-thirds of the fungal infections occurred in diabetic patients and 85% occurred in overweight or obese patients, suggesting that antifungal prophylaxis may be appropriate in these patients. STRENGTHS & LIMITATIONS: This is the largest series of fungal infections reported to date in the penile prosthesis literature. The overall number of such cases, however, remains small. CONCLUSION: Fungal infections represent 12% of all penile prosthesis infections in our series and were seen mostly in diabetic or overweight patients, who may benefit from antifungal prophylaxis. Gross MS, Reinstatler L, Henry GD, et al. Multicenter Investigation of Fungal Infections of Inflatable Penile Prostheses. J Sex Med 2019;16:1100-1105.