In this study of 503 consecutive cases of amebic liver abscess documented during a 21-year period, 110 (22%) were complicated by perforation. Perforation sites included pleuropulmonary structures (79 cases, 72%) subphrenic space (15 cases, 14%); and peritoneal cavity (11 cases, 10%). The less common sites were the thoracic and abdominal wall, pericardial sac, bile duct, kidney, mediastinum, colon, and right flank. Trophozoites were recovered in 29% of cases. For the rest of the cases, diagnosis was based on the clinical manifestations and the dramatic response to a therapeutic trial of amebicides. Open surgical drainage was done in 10 of 11 patients who had peritoneal perforation; 6 of them were cured and 5 died. Of 97 patients with perforation sites other than the peritoneal cavity, 64 were treated with metronidazole in addition to needle aspiration and/or percutaneous catheter drainage, and all achieved complete remission without relapse during subsequent follow-up. Of the 36 cases treated with metronidazole alone, 22 (61%) were cured. The mortality rate in the group with perforated abscess was 17% (19/110), compared with 5% (25/503) in the whole series. The results suggested that (1) amebic liver abscess can be difficult to diagnose, especially when the pathogen is not isolated; and (2) metronidazole combined with needle aspiration and/or percutaneous catheter drainage is the treatment of choice for amebic liver abscess with perforation.