Twenty heart transplant recipients were assayed serially with cytomegalovirus cultures and with Western blot techniques for development of anticytomegalovirus immunoglobulin M (IgM) and immunoglobulin G (IgG). Patients were followed up 3 to 29 months (mean, 15 months) after transplantation. All but three patients received a 5-week perioperative course of passive immunization with immune globulin. Of nine seronegative patients with seropositive grafts, positive cytomegalovirous cultures developed in all, secondary organ involvement (gastrointestinal or pneumonia) developed in four of nine. Four of nine patients produced limited IgM profiles, consisting of only one to three bands; six of the nine patients had atypical, restricted IgG profiles. Three of four patients in whom secondary organ invasion developed had limited IgM profiles, and all four had atypical IgG profiles. Four of five patients with primary infection without symptoms produced full IgM profiles. Delay of IgM production until a time coincident with or after evidence of viral shedding was documented in all patients with primary infection and secondary organ involvement. Among 11 seropositive patients, five received seropositive grafts and six seronegative grafts. Of the five patients with seropositive grafts, positive cultures (reinfection) developed in three; all three responded with full IgM profiles. However, secondary organ involvement developed in two of these three in spite of full IgM profiles. Symptomatic illness did not develop in any patient with a seronegative donor, even in the presence of positive cultures (reactivation). Persistence of IgM for up to 26 months was found in all patients with primary infection or reinfection. In heart transplant recipients, limited IgM and IgG profiles in primary infection may confer increased risk of secondary organ invasion whereas the early development of full IgM profiles may correlate with disease without symptoms. In seropositive patients, production of full IgM profiles may not protect from reinfection with secondary organ involvement if the organ donor is seropositive, a potential source of a new viral strain.