Newer immunosuppressive agents have dramatically reduced the rates of acute graft rejection (AR) over the last decade but may have exacerbated the problem of post-transplant infections (PTI). We analyzed data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) to determine the risks of hospitalization from PTI vs. AR in the years 1987–2000. For patients transplanted in 1987, the AR-associated hospitalization rate exceeded the equivalent hospitalization rate for PTI at both early (1–6 months) and later time points (6–24 months). In contrast, for patients transplanted in the year 2000, the PTI-associated hospitalization rate was twice that for AR-associated hospitalization during each time period. During the first two years post-transplant, rates of AR hospitalization trended significantly downwards (p < 0.001) while rates of PTI-associated hospitalization stayed constant. In the 6–24-month time period post-transplant, the risk of bacterial and viral infection-related hospitalization rose significantly from 1987 to 2000 (p < 0.001 for trend by transplant year). We conclude that the causes of hospitalization at all times up to 24 months post-transplant, including the critical early 6 months, have shifted away from AR to PTI.