Objective To compare the effect of erythromycin or metoclopramide on feed failure of mechanically ventilated patients in intensive care unit; to observe the effect of “rescue” combination therapy using both erythromycin and metoclopramide after monotherapy failure; to screen out the factors associated with a poor response to prokinetic therapy. Methods Seventy-two mechanically ventilated patients with feed failure in ICU from June 2007 to June 2010 were collected. Enteral nutrition was given at 10:00 on the first day after feed failure. The subjects were randomly divided into erythromycin group and metoclopramide group. The first erythromycin or metoclopramide injection was given at 8:00 on the first day. After 24 hours, gastric residual volume was aspirated and measured every day at 10:00, 16:00, 22:00 and 04:00 on next day. At the same time, we recorded the general condition and pretreatment 24-hour gastric residual volume of the subjects. The mean gastric residual volume and the successful feeding rate were compared every day. Six days later, the patients who failed the monotherapy received the rescue combination therapy directly for another 6 days. Twenty-four hours later, daily gastric residual volume and the successful feeding rate were recorded. Results For mechanically ventilated patients with feed failure, the daily gastric residual volume in erythromycin group was smaller than that in metoclopramide group[day 2:(75±19) vs (130±23) ml; day 3: (72±16) vs (120±21) ml; day 4: (71±22) vs (125±18) ml; P＜0.05]. The successful feeding rate in erythromycin group was higher than that in metoclopramide group(day 2:65.7% vs 37.8%; day 3: 51.4% vs 27.0%; day 4: 45.7% vs 18.9%; day 5:40.0% vs 16.2%; P＜0.05). In patients who failed monotherapy, the “rescue” combination therapy using erythromycin and metoclopramide had higher successful feeding rate(64.3% on day 5) than erythromycin(40%) or metoclopramide (16.2%). Factors that were associated with a poor response to prokinetic therapy included high pretreatment 24-hour gastric residual volume, high blood sugar, a high Acute Physiology and Chronic Health Evaluation Ⅱ (APACHEⅡ) score on inclusion day and the existence of any kinds of shock. Conclusion For mechanically ventilated patients with feed failure in ICU, erythromycin is more effective than metoclopramide; in patients who failed monotherapy, “rescue” combination therapy using erythromycin and metoclopramide is highly effective. High pretreatment 24-hour gastric residual volume, high blood sugar, a high APACHEⅡ score on inclusion day and existence of any kinds of shock are independent risk factors of a poor response to prokinetic therapy.