Background The use of prokinetic agents on post-pyloric insertion of spiral nasojejunal tubes is controversial.Aim The aim of the present study was to examine if metoclopramide or domperidone can increase the success rate of post-pyloric insertion of spiral nasojejunal tubes.Methods Multicenter, open-label, randomized, controlled trial in seven hospitals in China between April 2012 and April 2014.Patients admitted in the intensive care unit and requiting enteral nutrition for more than three days were randomly assigned to the metoclopramide, domperidone or control groups (1∶1∶1 ratio).The primary outcome was the success rate of reaching the duodenum (post-pyloric, D1) of spiral nasojejunal tubes, assessed 24 hours after initial placement.Secondary outcomes included success rate of reaching D2, D3, D4 and proximal jejunum and migration distance.Safety and tolerability of the study drugs and the tubes were assessed at insertion and 24 hours later.Results Three hundred-seven patients were allocated to the metoclopramide (n=103), domperidone (n=100) or control group (n=104).The success rate ofpost-pyloric migration after 24 hours in the metoclopramide, domperidone and control groups was 55.0%, 51.5% and 27.3%, respectively (P=0.0001).Logistic regression analysis identified the use of prokinetic agents, APACHE Ⅱ score <20, SOFA score <12 and without vasopressor as independent factors influencing the success rate of the feeding rube migration.No serious drug-related adverse reaction was observed.Conclusions Prokinetic agents such as metoclopramide or domperidone may be effective in improving the success rate of post-pyloric insertion of spiral nasojejunal tubes in critically ill patients.