Little information is available about the efficacy of proton pump inhibitors (PPIs) in patients with nonerosive reflux disease (NERD). We aimed to synthesize available data and determine the effectiveness of PPIs on symptom resolution in patients with NERD. A systematic review of the literature identified studies reporting the effects of PPIs in patients with NERD. Heartburn resolution data were pooled across studies. The effectiveness of PPI therapy in inducing complete heartburn resolution was compared in patients with NERD vs. erosive esophagitis (EE). Seven trials evaluating heartburn resolution in NERD were identified. Higher proportions of patients reported achieving sufficient heartburn resolution compared with complete heartburn resolution. The effect of PPIs on sufficient heartburn resolution was observed sooner than was complete heartburn resolution. Therapeutic gain of PPI therapy over placebo ranged from 30% to 35% for sufficient heartburn control and from 25% to 30% for complete heartburn control. Pooled response rates at 4 weeks were significantly higher for patients with EE compared with NERD (56% vs. 37%, P < 0.0001). PPIs provide a more modest therapeutic gain in patients with NERD as compared with those with EE. A trend in increased therapeutic gain for NERD patients was shown throughout the 4 weeks, suggesting that 4 weeks of follow-up evaluation may be insufficient to show full therapeutic gain in this patient population.