The etiologic evaluation of pericardial effusion is frequently unsuccessful when noninvasive methods are used. To determine the cause of the current episode, all patients with echographically identified pericardial effusion from May 1998 to December 2002 underwent noninvasive diagnostic testing of blood, throat, and stool samples. Patients with postpericardiotomy syndrome were excluded. To analyze the value of our tests, we tested randomly selected blood donors as negative controls. Among 204 included patients, 107 (52.4%) had a final etiologic diagnosis: the etiology of 52 was highly suspected at first examination and later confirmed (thyroid deficiency, 5 cases; systemic lupus erythematous, 7; rheumatoid arthritis, 7; scleroderma, 3; cancer, 25; and renal insufficiency, 5). A definite etiologic diagnosis was made in 11 patients from pericardial fluid analysis (cancer, 5 cases; tuberculosis, 3; Streptococcus pneumoniae, Citrobacter freundii, and Actinomyces, 1 case each). Among 141 patients considered to have idiopathic pericarditis, 44 (32.1%) gained an etiologic diagnosis by our systematic testing strategy. This included serologic evaluation of serum (Coxiella burnetii, 10 cases; Bartonella quintana, 1; Legionella pneumophila, 1; Mycoplasma pneumoniae, 4; influenza virus, 1), viral culture of throat swabs (enterovirus, 8 cases; and adenovirus, 1), high-level antinuclear antibodies (>1/400, 3 cases), and thyroid-stimulating hormone (15 abnormal results). Antibodies to Toxoplasma and cytomegalovirus, enterovirus recovered from rectal swabs, and low-level antinuclear antibodies were seen with equal frequency in patients and controls.Using our evaluation strategy, the number of pericardial effusions classified as idiopathic was less than in other series. Systematic testing for Q fever, Mycoplasma pneumoniae, thyroid abnormalities, and antinuclear antibodies, accompanied by viral throat cultures, frequently enabled us to diagnose diseases not initially suspected in patients with pericardial effusion.