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Preparticipation health screening is recommended to detect individuals susceptible to serious adverse cardiovascular complications during exercise. Although expert opinion and best available scientific evidence have informed recent modifications, there remain limited experimental data to support or refute current practice. We therefore aimed to quantify the impact of change to the preparticipation health screening guidelines of the American College of Sports Medicine (ACSM) on risk classification and referral for medical clearance in a large cohort of undergraduate university students.Participants attended the laboratory on a single occasion to undergo preparticipation health screening. Information concerning health status was obtained via self-report questionnaire and objective physiological assessment with all data recorded electronically and evaluated against the ACSM screening guidelines (9th and 10th editions).Five hundred and fifty-three students completed the study. The 9th edition screening guidance resulted in 82 subjects (15%) classified as high risk, almost one-quarter (24%) classified as moderate risk, and almost two-thirds (61%) classified as low risk. In comparison, the updated 10th edition screening guidance resulted in a significant reduction in those previously classified as either high risk (5%) or moderate risk (2%), respectively. The majority of subjects (93%) were therefore cleared to begin a structured exercise program. Taken together, approximately one-third (32%) fewer medical referrals were required when applying the updated 10th edition guidance (χ24 = 247.7, P < 0.001).The updated ACSM 10th edition preparticipation screening guidance reduces medical referrals by approximately one-third. These findings are in keeping with previous reports and thus serve to consolidate and justify recent modification—particularly when applied to young adult or adolescent populations. The findings and arguments presented should be used to refine and inform future guidance.