Background: Open reduction and internal fixation is currently the accepted treatment for displaced Lisfranc joint injuries. However, even with anatomic reduction and stable internal fixation, treatment of these injuries does not have uniformly excellent outcomes. The objective of this study was to compare primary arthrodesis with open reduction and internal fixation for the treatment of primarily ligamentous Lisfranc joint injuries. Methods: Forty-one patients with an isolated acute or subacute primarily ligamentous Lisfranc joint injury were enrolled in a prospective, randomized clinical trial comparing primary arthrodesis with traditional open reduction and internal fixation. The patients were followed for an average of 42.5 months. Evaluation was performed with clinical examination, radiography, the American Orthopaedic Foot and Ankle Society (AOFAS) Midfoot Scale, a visual analog pain scale, and a clinical questionnaire. Results: Twenty patients were treated with open reduction and screw fixation, and twenty-one patients were treated with primary arthrodesis of the medial two or three rays. Anatomic initial reduction was obtained in eighteen of the twenty patients in the open-reduction group and twenty of the twenty-one in the arthrodesis group. At two years postoperatively, the mean AOFAS Midfoot score was 68.6 points in the open-reduction group and 88 points in the arthrodesis group (p < 0.005). Five patients in the open-reduction group had persistent pain with the development of deformity or osteoarthrosis, and they were eventually treated with arthrodesis. The patients who had been treated with a primary arthrodesis estimated that their postoperative level of activities was 92% of their preinjury level, whereas the open-reduction group estimated that their postoperative level was only 65% of their preoperative level (p < 0.005). Conclusions: A primary stable arthrodesis of the medial two or three rays appears to have a better short and medium-term outcome than open reduction and internal fixation of ligamentous Lisfranc joint injuries. Level of Evidence: Therapeutic Level I.