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Postoperative fever and pericardial-pleural reaction, designated postpericardiotomy syndrome (PPS), is a common complication of cardiac surgery involving entry into the pericardium. To determine whether the etiology of PPS is viral or immunologic, we undertook a prospective, triple-blind study of consecutive long-term survivors of intrapericardial surgery in the pediatric age group. We evaluated clinical evidence of syndrome and concurrent appearance of antiheart antibody (AHA) by indirect immunofluorescence and antiviral antibody (AVA) by complement fixation in sera preoperatively and serially postoperatively. Incidence of PPS was 27% overall in 400 subjects, but only 3.5% in infants younger than 2 years of age. AHA in high titer appeared in all patients with PPS. A fourfold or greater rise in titer to AVA was found in 70% of these but in only 5% of those with negative AHA and no PPS. AVA rise, tested in 280 consecutive patients, was to no single one of the eight viruses studied (adenovirus, cytomegalovirus, and coxsackievirus B 1-6). Instead, the rise and fall, consistent with antiviral response to a recent infection, was exhibited usually to one but occasionally to two or more viruses, and the viral prevalence changed from year to year, as did that in the community. The study suggests that concurrent fresh or reactivated viral illness plays a role in triggering the immunologic response that characterizes the PPS.