PURPOSE: Prolonged postoperative ileus (PPOI) after colorectal resection significantly impacts patients' recovery and hospital stay. Because treatment options for PPOI are limited, it is necessary to focus on prevention strategies. The aim of this study is to investigate risk factors associated with PPOI in patients undergoing colorectal surgery. METHODS: Data from all consecutive patients who underwent colorectal resection in our department were retrospectively analyzed from a prospective database over a 9-month period. PPOI was defined as the necessity to insert a nasogastric tube in a patient who experienced nausea and two episodes of vomiting with absence of bowel function. Multivariable analysis was performed considering a prespecified list of 16 potential preoperative risk factors. RESULTS: A total of 523 patients (mean age 59 years; 52.2% males) were included, and 83 patients (15.9%) developed PPOI. Statistically significant independent predictors of PPOI were male sex (OR 2.07; P = 0.0034), open resection (OR 4.47; P < 0.0001), conversion to laparotomy (OR 4.83; P = 0.0015), splenic flexure mobilization (OR 1.72; P = 0.063), and rectal resection (OR 2.72; P = 0.0047). Discriminative ability of this prediction model was 0.72. CONCLUSIONS: Therapeutic strategies aimed to prevent PPOI after colorectal resection should focus on patients with increased risk. Patients and medical staff can be informed of the higher PPOI risk, so that early treatment can be started.