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This study compared clinical and radiographic results between patients who underwent stabilization of an acutely injured syndesmosis with a suture button (SB) and those treated with 1 quadricortical syndesmotic screw (SS).Ninety-seven patients, 18 to 70 years old, with an ankle injury that included the syndesmosis were randomized to 2 groups: SB (48 patients) and SS (49). The main outcome measure was the score on the American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot scale. The secondary outcome measures were the Olerud-Molander Ankle (OMA) score, visual analog scale (VAS), and EuroQol-5D (EQ-5D) Index and VAS. Computed tomography (CT) scans of both ankles were obtained at 2 weeks and 1 and 2 years after surgery. Both groups were allowed partial weight-bearing at 2 weeks and full weight-bearing at 6 weeks. The mean time for SS removal was 85.9 days (range, 39 to 132 days) after surgery. The patients were followed at 6 weeks, 6 months, and 1 and 2 years. Two years of follow-up were completed for 87 (90%) of the patients (46 in the SB group and 41 in the SS group).The SS group had more injuries to the posterior malleolus than the SB group. At 2 years, the median AOFAS score was higher in the SB group than in the SS group (96 [interquartile range, or IQR, 90 to 100] versus 86 [IQR, 80 to 96]; p = 0.001), as was the median OMA score (100 [IQR, 95 to 100] versus 90 [IQR, 75 to 100]; p < 0.001). The SB group reported less pain during walking at 2 years than the SS group (median VAS score, 0 [IQR, 0 to 1] versus 1 [IQR, 0 to 2]; p = 0.008) and less pain during rest (median VAS score, 0 [IQR, 0 to 0] versus 0 [IQR, 0 to 1]; p = 0.04). There was no difference between treatments groups with regard to pain at night or during daily activities at 2 years. The SB group had a higher median EQ-5D Index score at 2 years (1.0 [IQR, 1 to 1] versus 0.88 [IQR, 0.8 to 1.0]; p = 0.005). Twenty of 40 patients in the SS group had a difference in the tibiofibular distance of ≥2 mm between the injured and uninjured ankles at 2 years, compared with 8 of 40 in the SB group (p = 0.009). Seven patients in the SS group had symptomatic recurrent syndesmotic diastasis during the treatment period compared with none in the SB group (p = 0.005).The patients treated with an SB had higher AOFAS scores, OMA scores, and EQ-5D Index scores as well as lower (better) VAS scores for pain during walking and pain during rest. Also, the SB group had less widening seen radiographically at 2 years than did the patients in the SS group. No differences in the scores for pain at night or during daily activities were identified.Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.