BACKGROUND: A simplified dosing regimen may improve drug compliance in kidney transplant recipients and long-term graft outcomes. We aimed to identify, appraise, and synthesize the current evidence comparing the relative safety and efficacy of the recently introduced daily versus standard twice-daily tacrolimus administration. METHODS: We systematically reviewed all randomized controlled trials and observational studies that compared the outcomes of daily versus twice-daily tacrolimus formulation in kidney transplant recipients. Medline (from 1948 to July week 4 2011), Embase (1980 to 2011 week 31), the Cochrane Library (1991 to June 2011), and conference proceedings were searched without language restriction. RESULTS: Six randomized controlled trials (n=2499) and 15 observational studies (n=2886) were included in the review. There were no significant differences in biopsy-proven acute rejection (two trials, n=1093; risk ratio [RR; confidence interval (CI)], 1.24 [0.93-1.65]; P=0.15; I=0%), patient survival (three trials, n=1156; RR [CI], 0.99 [0.97-1.02]; P=0.55; I=32%), and graft survival (three trials, n=1156; RR [CI], 0.99 [0.97-1.02]; P=0.67; I=0%) between the two formulations at 12 months. Similar results for acute rejection (five studies, n=391; RR [CI], 0.99 [0.93-1.06]; P=0.84; I=0%) and overall patient survival (two studies, n=218; RR [CI], 1.02 [0.94-1.10]; P=0.62; I=0%) were observed in observational studies. CONCLUSIONS: Once-daily tacrolimus appears to be as effective as twice-daily tacrolimus up to 12 months after kidney transplantation.