BACKGROUND Delaying initiation of tacrolimus after liver transplantation (LT) is a potential renal-sparing strategy. We assessed safety and efficacy of delayed initiation of prolonged-release tacrolimus (PR-T) in de novo LT. MATERIAL AND METHODS This was a single-center, single-arm, prospective, 12-month observational study of hepatitis C virus-negative orthotopic LT patients. Immunosuppression included PR-T (initially 0.1 or 0.2 mg/kg/day) initiated on Day 3 post LT, basiliximab (20 mg) on post-transplantation Day 0 and Day 4, and intraoperative corticosteroids (500 mg). Patients received maintenance corticosteroids and mycophenolate mofetil (MMF) according to center protocol. MMF dose was adjusted according to thrombocyte count. The primary endpoint was the estimated glomerular filtration rate (eGFR) measured using the Modification of Diet in Renal Disease 4-variable formula at 12 months. Secondary endpoints included biopsy-confirmed acute rejection (BCAR) and dialysis requirement. Adverse events were recorded. RESULTS Sixty-nine patients (mean age 55.0 years) were included. Most patients started MMF on Day 1 (60.9%) or Day 2 (10.1%), and PR-T on Day 3 (55.1%) or Day 4 (29.0%). Mean tacrolimus trough levels (ng/mL) were: Day 7, 9.5±6.3; Day 10, 9.4±5.4; Month 1, 8.0±3.1; Month 3, 7.8±3.7; Month 6, 8.0±4.1; and Month 12, 7.2±3.1. Mean 12-month eGFR was 77.2±24.5 mL/min/1.73 m2; 72.5% of patients had eGFR >60 mL/min/1.73 m² at 12 months; 89.9% had no eGFR measurements <40 mL/min/1.73 m² during the study. Renal insufficiency (any eGFR <60 mL/min/1.73 m²) was diagnosed in 27.5% of patients; one patient required dialysis. There were no BCAR episodes; the infection rate was 36.2%, and 3 patients died. Overall, 19 patients (27.5%) developed de novo diabetes mellitus, 18 patients (26.1%) had hypercholesterolemia, and 12 patients (17.4%) had hypertriglyceridemia. CONCLUSIONS Quadruple therapy with delayed administration of PR-T was well tolerated and efficacious, and was associated with acceptable renal function over 12 months.