Background & Aims: Studies have demonstrated that gastroesophageal reflux disease (GERD) can cause sleep deprivation because of nighttime heartburn or short, amnestic arousals during sleep. Sleep deprivation has been associated with reports of increased GERD severity. Our aim was to determine whether sleep deprivation enhances perception of intraesophageal acid in patients with GERD vs healthy controls. Methods: Ten healthy controls and 10 patients with erosive esophagitis (grades B-D) were included in the study. All subjects were randomized to either sleep deprivation (1 night with ≤3 hours of sleep) or sufficient sleep (3 days with ≥7 hours sleep/night). Patients crossed over to the other arm after a washout period of 1 week. To ensure proper sleep time, we objectively monitored subjects with an actigraph. The morning after sufficient sleep or sleep deprivation, patients underwent stimulus response functions to esophageal acid perfusion. Results: Ten healthy controls and 10 GERD patients completed all stages of the study. GERD patients demonstrated a significant decrease in lag time to symptom report (91 ± 21.6 vs 282.7 ± 67 sec, respectively, P = .02), increase in intensity rating (9.3 ± 1.4 vs 4.4 ± 0.9 cm, respectively, P = .02), and increase in acid perfusion sensitivity score (48.3 ± 8.5 vs 22.7 ± 4.5 sec × cm/100, respectively, P = .02) after sleep deprivation as compared with nights of good sleep. Normal subjects did not demonstrate any differences in stimulus response functions to acid between sufficient sleep and sleep deprivation (578 ± 164 vs 493.8 ± 60.3 sec, 0.3 ± 0.2 vs 0.45 ± 0.2 cm, and 0.4 ± 0.3 vs 2.4 ± 1.4 sec × cm/100, respectively, all P = NS). Conclusions: Sleep deprivation is hyperalgesic in patients with GERD and provides a potential mechanism for increase in GERD symptom severity in sleep-deprived patients.