To determine the possible association of Chlamydia pneumoniae infection and reactive airway disease in children. Prospective observational study. Pediatric emergency department in Children's Medical Center of Brooklyn (NY), Kings County Hospital Center. One hundred eighteen children with acute episodes of wheezing and 41 age- and sex-matched healthy controls, aged 5 to 16 years. Children with cultures positive for C pneumoniae were treated with antibiotics. Cultures for C pneumoniae and serum samples for antibody testing were obtained from subjects and healthy controls. We isolated C pneumoniae from 13 (11%) children with wheezing and from two (4.9%) controls. Seven (58.3%) of 12 children with positive cultures had no detectable antibody to C pneumoniae and only three (25%) children had serologic evidence of acute infection. Six children had positive cultures on multiple occasions, ranging from 1 to 5 months. The children with wheezing were treated with erythromycin or clarithromycin, a new macrolide antibiotic approved for use in adults; all eventually had a negative culture. Nine (75%) of these children demonstrated clinical and laboratory improvement of the reactive airway disease after the eradication of chlamydial infection. Infection with C pneumoniae can trigger acute episodes of wheezing in children with asthma. Treatment of C pneumoniae infection may improve the course of reactive airway disease in these patients.