For a study, the researchers sought to determine if early drain removal (EDR) may reduce the occurrence of grade 2 to 4 problems in patients undergoing pancreaticoduodenectomy (PD) with a low or moderate risk of pancreatic fistula (POPF) after surgery. A multicenter randomized controlled experiment was conducted at 6 tertiary referral hospitals. Patients who met the inclusion criteria included a drain amylase level of less than 5000 U/L on a postoperative day (POD) 1 and POD 3 and a drain output of fewer than 300 mL per day within 3 days of surgery. Patients were subsequently assigned to 1 of 2 groups: EDR or RDR (regular drain removal). On POD3, all drainage tubes in the EDR group were removed. Drainage tubes were removed from the RDR group on POD 5 or later. The occurrence of Clavien-Dindo grade 2 to 4 problems was the primary outcome. Within 90 days following surgery, secondary outcomes included the complete complication index, grade B/C POPF, total medical expenses, and postoperative in-hospital stay. About 692 patients were screened, with 312 of them being suitable for randomization. The 2 groups had similar baseline characteristics, and according to the 10-point fistula risk score, 96.8% of the 312 patients had a low or moderate risk of POPF. In the EDR group, 20.5% of patients experienced at least 1 grade 2 to 4 complication, compared to 26.3% in the RDR group (P=0.229). Older age (>65 years old) and blood transfusion were independent risk factors for grade 2 to 4 problems in multivariate analyses. In both groups, the rate of grade B/C POPF was low (3.8% vs 6.4%, P=0.305). The 2 groups’ comprehensive complication indexes were similar (20.9 vs 20.9, P=0.253). The total medical costs did not differ considerably. After surgery, the length of stay in the hospital was clinically similar (15 days vs 16 days, P=0.010). Almost half of the PD patients matched the inclusion criteria, indicating a low risk of grade B/C POPF and significant sequelae. EDR was safe in these patients; however, it did not affect serious problems.