OBJECTIVE: To determine the effectiveness of coach-led neuromuscular warm-up on reducing lower extremity (LE) injuries in female athletes in a mixed-ethnicity, predominantly low-income, urban population. DESIGN: Cluster randomized controlled trial. SETTING: Chicago public high schools. PARTICIPANTS: Of 258 coaches invited to participate, 95 (36.8%) enrolled (1558 athletes). Ninety coaches and 1492 athletes completed the study. INTERVENTIONS: We randomized schools to intervention and control groups. We trained intervention coaches to implement a 20-minute neuromuscular warm-up. Control coaches used their usual warm-up. MAIN OUTCOME MEASURES: Coach compliance was tracked by self-report and direct observation. Coaches reported weekly athlete exposures (AEs) and LE injuries causing a missed practice or game. Research assistants interviewed injured athletes. Injury rates were compared between the control and intervention groups using chi(2) and Fisher exact tests. Significance was set at P < .05. Poisson regression analysis adjusted for clustering and covariates in an athlete subset reporting personal information (n = 855; 57.3%). RESULTS: There were 28 023 intervention AEs and 22 925 control AEs. Intervention coaches used prescribed warm-up in 1425 of 1773 practices (80.4%). Intervention athletes had lower rates per 1000 AEs of gradual-onset LE injuries (0.43 vs 1.22, P < .01), acute-onset noncontact LE injuries (0.71 vs 1.61, P < .01), noncontact ankle sprains (0.25 vs 0.74, P = .01), and LE injuries treated surgically (0 vs 0.17, P = .04). Regression analysis showed significant incidence rate ratios for acute-onset noncontact LE injuries (0.33; 95% CI, 0.17-0.61), noncontact ankle sprains (0.38; 95% CI, 0.15-0.98), noncontact knee sprains (0.30; 95% CI, 0.10-0.86), and noncontact anterior cruciate ligament injuries (0.20; 95% CI, 0.04-0.95). CONCLUSION: Coach-led neuromuscular warm-up reduces noncontact LE injuries in female high school soccer and basketball athletes from a mixed-ethnicity, predominantly low-income, urban population. Trial Registration clinicaltrials.org Identifier: NCT01092286.