Objective: To compare clinical, health-related quality of life (HRQL), and medical cost outcomes in patients with symptomatic gastroesophageal reflux disease (GERD) receiving omeprazole sodium or ranitidine hydrochloride treatment., Methods: A multicenter, randomized, open-label, medical effectiveness trial conducted in 5 university-based family medicine clinics. Two hundred sixty-eight patients with GERD were recruited and randomly assigned to omeprazole sodium, 20 mg once daily, or ranitidine hydrochloride, 150 mg twice daily, for up to 6 months. Main outcome assessments included the Gastrointestinal Symptom Rating Scale (GSRS) Reflux score, Psychological General Well-Being Index, and Short-Form-36 Health Survey administered at baseline and 2, 4, 12, and 24 weeks. Medical resource use and cost data were collected., Results: More omeprazole-treated patients reported improved heartburn resolution at 2 weeks (49.0% vs 33.3%; P=.007) and 4 weeks (58.6% vs 35.0%; P<.001) compared with ranitidine-treated patients. The GSRS Reflux scores across 3 months showed overall differences between omeprazole (mean, 2.67) and ranitidine (mean, 2.95) groups (P=.04). Mean total 6-month medical costs were $915 lower ($8371 vs $9286; P=.64), and no difference in mean outpatient medical costs ($1198 vs $1158; P=.76) were observed in the omeprazole group compared with the ranitidine group. A post hoc secondary analysis showed that, at 12 and 24 weeks, patients treated with omeprazole for 8 weeks or more reported greater heartburn resolution (ie, 24 [43%] of 56 patients at both intervals) than patients treated with ranitidine for 8 weeks or more (12 [24%] and 13 [26%] of 50 patients, respectively; P=.001)., Conclusions: Ranitidine and omeprazole were both effective at improving heartburn symptoms; however, omeprazole provided greater resolution of heartburn symptoms at 2 and 4 weeks. Despite omeprazole's higher acquisition cost, there were no significant differences in total or outpatient costs between groups.