Although the pathogenic mycoplasmas usually infect the respiratory and urogenital tracts, these organisms also can cause disease in remote sites. Such infections are difficult to diagnose because of both the fastidious nature of the mycoplasmas and the failure to consider their presence. Pericarditis is an uncommonly diagnosed and rarely confirmed example of invasive mycoplasmal infection. As part of a prospective study of large pericardial effusions, we discovered two cases with Mycoplasma pneumoniae infection. Subsequently, two cases of pericarditis due to Mycoplasma hominis and one due to Ureaplasma urealyticum were diagnosed. For all five patients, cultures of pericardial tissue and/or fluid were positive. In addition, four of the five patients either were immunocompromised or had undergone cardiac surgery previously. Appropriate antibiotic therapy was uniformly effective. We report here our experience with mycoplasmal pericarditis, provide evidence of an invasive pathogenesis for this syndrome, and suggest that pericardial disease caused by these organisms may not be an uncommon finding when sought in an aggressive manner.