The primary aim of the study was to investigate the generic health-related quality of life (HRQOL) of pediatric patients meeting Rome II criteria for irritable bowel syndrome (IBS) in comparison to healthy children. The secondary aim was to compare pediatric patients with IBS to pediatric patients with Rome II criteria diagnosed functional abdominal pain (FAP) and patients with diagnosed organic gastrointestinal (GI) disorders. The study also investigated the associations between GI symptoms with generic HRQOL and evaluated group differences in school days missed and days sick in bed and needing care. HRQOL was measured with the PedsQLtrade mark 4.0 Generic Core Scales (Physical, Emotional, Social, and School Functioning). The PedsQLtrade mark was administered in outpatient pediatric gastroenterology clinics in California, Texas, and New Jersey. A total of 287 families (280 child self-report, 286 parent proxy-report) with children diagnosed with IBS (n = 123), FAP (n = 82), or organic GI disorders (n = 82) participated. Pediatric patients with IBS demonstrated significantly lower Physical, Emotional, Social, and School Functioning in comparison to healthy children, and comparable HRQOL to patients with FAP and organic GI diagnoses. GI symptoms were significantly associated with generic HRQOL. Patients with IBS demonstrated a significantly greater number of days missed from school, days sick in bed/too ill to play, and days needing someone to care for them than healthy children, but significantly fewer days than patients with FAP and organic GI disorders. Pediatric patients with IBS demonstrated impaired HRQOL in dimensions measuring Physical, Emotional, Social, and School Functioning. These findings suggest the need for targeted interventions to address these dimensions of impaired HRQOL.