The ideal aortic valve substitute in young and middle-aged adults remains unknown. To compare long-term outcomes between the Ross procedure and mechanical aortic valve replacement in adults. The Ovid versions of MEDLINE and EMBASE classic (January 1, 1967, to April 26, 2018; search performed on April 27, 2018) were screened for relevant studies using the following text word search in the title or abstract: ("Ross" OR "autograft") AND ("aortic" OR "mechanical"). All randomized clinical trials and observational studies comparing the Ross procedure to the use of mechanical prostheses in adults undergoing aortic valve replacement were included. Studies were included if they reported any of the prespecified primary or secondary outcomes. Studies were excluded if no clinical outcomes were reported or if data were published only as an abstract. Citations were screened in duplicate by 2 of the authors, and disagreements regarding inclusion were reconciled via consensus. This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis of Observational Studies in Epidemiology guidelines. Data were independently abstracted by 3 reviewers and pooled using a random-effects model. The prespecified primary outcome was all-cause mortality. The search identified 2919 reports, of which 18 studies (3516 patients) met inclusion criteria, including 1 randomized clinical trial and 17 observational studies, with a median average follow-up of 5.8 (interquartile range, 3.4-9.2) years. Analysis of the primary outcome showed a 46% lower all-cause mortality in patients undergoing the Ross procedure compared with mechanical aortic valve replacement (incidence rate ratio [IRR], 0.54; 95% CI, 0.35-0.82; P = .004; I2 = 28%). The Ross procedure was also associated with lower rates of stroke (IRR, 0.26; 95% CI, 0.09-0.80; P = .02; I2 = 8%) and major bleeding (IRR, 0.17; 95% CI, 0.07-0.40; P < .001; I2 = 0%) but higher rates of reintervention (IRR, 1.76; 95% CI, 1.16-2.65; P = .007; I2 = 0%). Data from primarily observational studies suggest that the Ross procedure is associated with lower all-cause mortality compared with mechanical aortic valve replacement. These findings highlight the need for a large, prospective randomized clinical trial comparing long-term outcomes between these 2 interventions.