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To determine the efficacy and safety of periarticular hyaluronic acid injections in acute lateral ankle sprain during 9 months at a sports injuries center.Randomized controlled prospective trial.Primary sport medicine and emergency practice.One hundred fifty-eight consecutive competitive athletes who suffered acute grade 1 or 2 lateral ankle sprains were randomized within 48 hours of injury.Patients were randomized at baseline to periarticular injection with hyaluronic acid (HA) + standard of care [rest, ice, compression, and elevation (RICE)] or placebo injection (PL) + standard of care (RICE) treatment at baseline assessment and on day 4 after injury.Assessments at baseline and days 4, 8, 30, and 90 included Visual Analogue Scale (VAS; 0-10 cm) pain on weight bearing and walking 20 m, patient global assessment of ankle injury (five-point categorical scale), patient satisfaction with treatment (five-point categorical scale), time to return to pain-free and disability-free sport, and adverse events. Differences between groups were determined using an intent-to-treat analysis of variance.About 30% of the ankle sprains were “first” events, and no differences in clinical assessments with those presenting but not volunteering for the study (n = 341) were observed. Time to intervention was 39 ± 4 hours, with no difference between groups. No serious adverse events were recorded during the 8-day treatment period. No difference in concomitant treatment or physical therapy was observed between groups. A significant reduction in VAS pain on both weight bearing and walking was observed at day 8 for HA compared with PL (P < 0.05). Significantly greater patient satisfaction was observed for HA versus PL at days 4 (P < 0.05), 8 (P < 0.001), 30 (P < 0.001), and 90 (P < 0.05). Patient global assessment of ankle injury was significantly better compared with baseline in the HA group at day 8, but this was not different between groups. Time to pain-free and disability-free return to sport was 11 (±8) versus 17 (±8) days for HA and PL, respectively (P < 0.05).HA treatment for acute ankle sprain was highly satisfactory in the short term and the long term versus PL. This was associated with reduced pain and more rapid return to sport, with few associated adverse events.