To evaluate the effectiveness of the role of advanced nurse practitioners compared to physicians-led/ usual care (care managed by medical doctors or non-advanced nurse practitioners). Advanced nurse practitioners contribute to the improvement of quality patient care and have substantial potential to optimise the health of people globally. Since the formal recognition of advanced nurse practitioners by the International Council of Nurses, among others, the role has been adopted across most departments and clinical specialties, particularly in high-income countries. Systematic review of primary research evidence. MEDLINE, EMBASE, CINAHL, Cochrane registry, Cochrane trials, and Cochrane EPOC (PDQ Evidence) were searched for randomised controlled trials (RCTs) of patient care and health resource utilisation outcomes associated with advanced nurse practitioners. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The chosen articles were restricted to full-text English language trials published in the last 20 years, incorporating comparators of usual care. Search terms were limited to variations of advanced nurse practitioner role and practice. The eligible studies were bias risk assessed and quality assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Clinical and service outcomes were analysed using narrative synthesis as the marked heterogeneity between studies precluded meta-analysis. Thirteen RCTs were reviewed. All of them were conducted across high-income countries within primary care and hospital settings involving paediatric and adult patients. Five trials were assessed as high quality, and eight were of low to moderate quality. Positive effects were demonstrated for the impact of advanced nurse practitioners on usual care; for indigestion, mean difference [MD] 2.3: 95% CI 1.4, 3.1]), perceptions of health status [ (MD -140.6; 95% CI -184.8, -96.5)], satisfaction levels [ (MD ranged from -8.79; 95% CI -13.59, -3.98 to 0.61; 95% CI -4.84, 6.05)], physical function (1.58 [SD 0.76] v. 1.81 [SD 0.90]), and blood pressure control (systolic [133 [SD 21] v. 135 [SD 19] mmHg p=0.04] and diastolic [77 [SD 10] v. 80 [SD 11] mmHg p=0.007]) were looked at. Positive effects related to service provision included improved patient satisfaction and reductions in waiting times and costs, which significantly favored advanced nurse practitioners (all p<0.05). The evidence of this review supports the positive impact of advanced nurse practitioners on clinical and service-related outcomes: patient satisfaction, waiting times, control of chronic disease, and cost-effectiveness especially when directly compared to medical practitioner-led care and usual care practices - in primary, secondary and specialist care settings involving both adult and pediatric populations.