In pig‐to‐baboon xenotransplantation, porcine cytomegalovirus (PCMV) causes viremia, consumptive coagulopathy, and tissue‐invasive disease. Baboon cytomegalovirus (BCMV) is associated with invasive disease in xenograft recipients. The efficacy of prophylaxis with intravenous ganciclovir (GCV) was studied for prevention of PCMV and BCMV infections in pig‐to baboon xenotransplantation. GCV prophylaxis did not alter the incidence of BCMV activation in recipients, but reduced the amount of virus in tissues (mean 8.38 × 102 vs. 3.24 × 105 copies/µg DNA without treatment) and prevented tissue‐invasive infections. PCMV viral loads were unaltered by GCV prophylaxis (8.36 × 108 copies/µg DNA without prophylaxis vs. 1.20 × 109 copies/µg DNA with prophylaxis). In vitro, PCMV was relatively resistant to GCV [90% inhibitory concentration (IC90) of 10 µm, IC50 = 3 µm], acyclovir (100 µm), and leflunomide (not achievable). Only cidofovir (IC90 1 µm) and foscarnet (IC90 100 µm) might have therapeutic efficacy for PCMV in vivo in achievable concentrations, although these agents often carry significant toxicity in transplant recipients. GCV has limited activity against BCMV and no therapeutic efficacy against PCMV at standard doses in vivo. GCV and other antiviral agents have limited activities against PCMV in vitro. Breeding of PCMV‐free xenograft donors may be necessary to prevent PCMV infections in clinical trials.