Randomized clinical trials for patients with invasive fungal infections (IFIs) are often limited or precluded, necessitating alternate sources of information. The Prospective Antifungal Therapy Alliance (PATH Alliance) is a registry that collects data on patients with IFIs at medical centers in North America. Patients with a diagnosis of proven or probable IFI are enrolled and followed prospectively for 12 weeks. Using a Web-based electronic data capture and reporting system, the registry collects anonymous data to address end points in epidemiology, diagnosis, treatment, and outcome of IFIs. As of October 2006, 1892 IFIs were observed in 1710 patients enrolled at 22 sites. The most commonly encountered IFIs were caused by Candida spp. (73.0%), presenting predominantly as candidemia, followed by Aspergillus spp. (14.8%). A small number of IFIs with uncommon and emerging moulds were observed. Culture remains the main diagnostic tool for most IFIs (91.8%). Antifungal agent choice depended on the fungal species isolated, with fluconazole being the most frequently administered agent (58.2%). The overall crude 12-week mortality, excluding the patients lost to follow-up, was 43.9%. PATH Alliance is a network of medical institutions gathering significant information about IFIs in North America. Significant trends and treatment practices concerning yeasts and moulds were observed. As enrollment continues, additional data will be analyzed and published, which will provide valuable information concerning the epidemiology, therapy, and outcomes of IFIs.