Background: We analyzed bacterial and fungal infectious complications in a cohort of 16 consecutive experiments with the longest surviving cardiac xenografts to date. Methods: Transgenic, porcine-to-baboon, heterotopic (abdomen) cardiac xenotransplantation was performed in 16 consecutive experiments, using rapamycin, tacrolimus, corticosteroids, anti-CD20 monoclonal antibody, and an alpha-Gal-PEG polymer, as immunosuppression. Prophylactic anti-microbials included i.v. trimethoprim/sulfamethoxazole, oral ganciclovir/valganciclovir, and oral itraconazole. An episode of bacterial infection was denned as a positive blood and/or wound culture with: leukocytosis, fever > 101.5°F, and/or clinical deterioration. Results: Mean graft survival was 71 ± 29 days; the longest was 113 days. There were 23 episodes of bacterial infection; 14 resolved with treatment. The mean time to the first episode of infection was 44 ± 21 days (n = 12). Eight of 16 deaths were due to infection: two bacterial-only, two cytomegalovirus (CMV) only, four both bacterial and CMV, and none fungal. The frequency of infection was 1, 2.8, and 1.8 episodes/100 survival days, respectively, for animals whose grafts survived for 30 to 59, 60 to 89, and > 90 days. CMV infection (reviewed in detail in a separate communications) was due to baboon CMV, and was associated with low serum levels of ganciclovir. Conclusion: In a cardiac xenograft model that achieved prolonged (> 3 months) survival, bacteremia was common, but usually reversible, and fungal infection was prevented with prophylaxis. The level of immunosuppression required to achieve clinically meaningful xenograft survival is associated with a level of bacterial and fungal infectious complications that is manageable and similar to the early clinical experiences in human transplantation. Further research will determine if the viral infectious complications observed in these experiments can be reduced by optimizing blood levels of anti-viral prophylaxis and monitoring viral polymerase chain reaction levels. © Blackwell Munksgaard, 2005.