Background: Placebo-controlled studies have indicated that both cisapride and metoclopramide promote gastric motility in critically ill patients. Objective: This study was conducted to compare cisapride and metoclopramide for facilitating gastric emptying and improving tolerance to intragastric enteral nutrition (EN) and to evaluate the relationship between aspirated gastric residual volume and gastric emptying function in this patient population. Methods: In this double-blind study, critically ill, mechanically ventilated patients with an aspirated gastric residual volume ≥150 mL while receiving intragastric EN were randomized to receive enteral cisapride 10 mg or metoclopramide 10 mg every 6 hours for a total of 7 doses. The acetaminophen-absorption method was used to assess gastric emptying at baseline and 30 minutes after the seventh dose by determining the area under the plasma concentration—time curve at 240 minutes (AUC 240), maximum concentration (C max), and time to C max (T max). Gastric residual volume was measured every 6 hours before dosing. Results: Fourteen patients were included in the study, 7 in each group. Patient characteristics were similar in the 2 groups. Compared with baseline, metoclopramide significantly accelerated T max (39.00 ± 15.56 min with metoclopramide vs 103.71 ± 47.35 min at baseline; P = 0.018) and increased C max (12.94 ± 6.68 mg/L vs 6.97 ± 4.78 mg/L; P = 0.018) and AUC 240 (1421.43 ± 780.31 mg/L·min vs 839.00 ± 545.58 mg/L·min; P = 0.043). Cisapride increased C max from baseline (12.27 ± 8.95 mg/L vs 4.53 ± 2.37 mg/L, respectively), but the difference was not statistically significant. Gastric residual volume was significantly reduced from baseline after 3 doses of metoclopramide (from 268.7 ± 112.3 mL to 57.0 ± 23.1 mL; P < 0.05) and was significantly lower after the seventh dose of metoclopramide than after the seventh dose of cisapride (5.3 ± 8.2 mL vs 41.4 ± 39.7 mL, respectively; P = 0.05). C max at baseline and residual volume at study entry were inversely correlated ( r = −0.50; P = 0.049). Conclusions: Both cisapride and metoclopramide enhanced gastric motility and improved tolerance to intragastric EN. Metoclopramide reduced gastric residual volume to a significantly greater extent than did cisapride. Only C max at baseline was inversely associated with residual volume.