We determined prospectively during a 12-month period the incidence, clinical characteristics and outcome of Yersinia enterocolitica infection in 144 thalassemic patients (mean age, 12.8 years) and compared them with 100 controls (mean age, 12.1 years). Symptomatic Y. enterocolitica infection occurred in 14 (10%) of the thalassemic patients and in 2 (2%) controls (P = 0.017). Of the 14 thalassemic patients 5 (36%) had septicemia and 9 (64%) had focal infection (enteritis in 8 and tonsillitis in 1). One control patient had acute enteritis and the other had tonsillitis. All isolates from these patients belonged to pathogenic phenotypes of Y. enterocolitica. Pending culture results symptomatic thalassemic patients discontinued treatment with deferoxamine and were treated with intravenous antibiotic therapy. Patients with the ultimate diagnosis of focal Y. enterocolitica infection continued treatment with intramuscular ceftriaxone or intravenous trimethoprim/sulfamethoxazole (TMP/SMX) for 7 days, whereas those with septicemia continued treatment with intravenous TMP/SMX for 14 days. The outcome was favorable in all 14 thalassemic patients. We conclude that Y. enterocolitica is a significant cause of morbidity in our patients with thalassemia and that prompt antibiotic therapy might prevent life-threatening conditions as well as a complicated course with long term sequelae.