We have previously shown that the preemptive use of cytomegalovirus (CMV) immunoglobulin (Ig) replacement (CytoGam) decreases the incidence of opportunistic infections in cardiac transplant recipients with severe hypogammaglobulinemia. However, the impact of Ig replacement in moderately hypogammaglobulinemic patients is unknown. Periodic monitoring of the IgG levels was done in 300 heart transplant recipients. Moderate hypogammaglobulinemia (IgG, 350-500 mg/dl) developed in 56 patients (18.6%). Thirty-three patients declined randomization but agreed to have their IgG levels monitored. Twenty-three patients were randomized to placebo (n = 10) or CytoGam (n = 13) at 105 +/- 63 days after transplantation. The baseline characteristics were similar. A significant reduction in CMV infection was noted in the CytoGam Group compared with the Placebo Group (15.4% 2/13 vs 60% 6/10, p = .039). Among patients who declined randomization, CMV infection developed in 13 (39.4%) of 33, and 6 (46.1%) of the 13 progressed to severe hypogammaglobulinemia. A trend for reduction in the average episodes of > or =grade 2 rejection during the 6-month period after randomization was noted in the CytoGam group (0.4 +/- 0.6 vs 1.4 +/- 1.3, p = 0.065). The preemptive use of CytoGam decreases the incidence of CMV infection in patients with moderate hypogammaglobulinemia. A larger randomized study is needed to substantiate these results.