We sought to determine whether quantitative assessment of anti-cytomegalovirus (CMV) antibodies could be useful to identify patients at risk of cytomegalovirus (CMV) disease after heart transplantation (HT). 75 patients who underwent HT at a single health care center were prospectively studied. Induction therapy included 2 doses of daclizumab and maintenance tacrolimus (n = 42) or cyclosporine (n = 29), mycophenolate mofetil and prednisone. All patients received prophylaxis with gancyclovir or valganciclovir. Anti-CMV intravenous immunoglobulin (CMV-IG) was added in high risk patients (CMV D+/R− serostatus). Serial determinations of anti-CMV antibodies, immunoglobulins (IgG, IgA, IgM) and IgG-subclasses were analysed. CMV infection was based on detection of the virus by antigenemia. CMV disease consisted of detection of signs or symptoms attributable to this microorganism. Ten patients (13.3%) developed CMV disease. Mean time of development of CMV disease was 3.4 ± 1.6 months. In Cox regression analysis, patients with low baseline anti-CMV titers (<4.26 natural logarithm of titer, RH: 8.1, 95%CI: 1.93-34.1, p = 0.004) and recipients with 1-month post-HT IgG hypogammaglobulinemia (IgG < 500 mg/dl, RH: 4.49, 95%CI: 1.26-15.94, p = 0.02) were at higher risk of having CMV disease. Despite use of prophylactic CMV-IG, D+/R− patients showed significantly lower titers of anti-CMV antibodies at 7 d, 30 d and 90 d post HT as compared with HT recipients without infections. Four out of 6 of these patients developed late CMV disease. Monitoring of specific anti-CMV antibodies on the bedside warrants further evaluation as a potential tool to identify heart transplant recipients at higher risk of CMV disease.