An estimated incidence of drug-induced lupus erythematosus caused by all drugs is 15,000 to 20,000 cases a year, and represents approximately 5 to 10% of the total number of patients with systemic lupus erythematosus. Approximately 22% of the patients treated with isoniazid for a mean of 6 months develop antinuclear antibodies. Isoniazid-induced lupus erythematosus affects either sex equally and the most common presenting feature is arthralgia or arthritis with anemia. Fever and pleuritis occur in approximately half of the cases, and pericarditis in approximately 30% of cases. IgG antibody to the (H2A-H2B)-DNA complex appears specific for the isoniazid-induced lupus erythematosus. The drug-induced lupus presenting with cardiac tamponade is a recognized feature of many drugs such as hydralazine, procainamide, and sulfasalazine. Reported here is a case of isoniazid-induced lupus erythematosus presenting with cardiac tamponade. A 73-year-old man was treated with isoniazid for 8 months at a dose of 300 mg a day. The patient responded to the withdrawal of the isoniazid therapy and placement of a pericardial window. The existing literature on the subject is reviewed.