The purpose of this study was to conduct a prospective outcome analysis of proximal tibial opening wedge osteotomies performed in young and middle-aged patients (aged <55 years) for the treatment of symptomatic medial compartment osteoarthritis of the knee. A consecutive series of young and middle-aged adults who underwent proximal tibial opening wedge osteotomies for symptomatic medial compartment osteoarthritis and genu varus alignment were prospectively followed up. Patients were evaluated with preoperative and postoperative modified Cincinnati Knee Scores and International Knee Documentation Committee objective knee subscores for knee effusions and the single-leg hop. Calculations were made of the preoperative and postoperative long-leg radiographic mechanical weight-bearing axis, patellar height (Insall-Salvati index), and tibial slope. A separate cohort of asymptomatic patients was used to quantify tibial plateau anatomy to provide an objective description of the lower extremity mechanical axis. There were 47 patients, with a mean age of 40.5 years, with a minimum of 2 years' follow-up, who formed this patient cohort. Modified Cincinnati Knee Scores improved significantly from 42.9 preoperatively to 65.1 at a mean of 3.6 years of follow-up. Radiographic analysis of a separate cohort showed the medial tibial eminence to be located at the 41% point along the tibial plateau from medial (0%) to lateral (100%). There was a significant improvement in malalignment: the mean mechanical axis passed through the tibial plateau at 23% of the distance along the proximal tibia preoperatively versus 54% postoperatively. The Insall-Salvati index decreased from 1.03 to 0.95 (P < .05), and posterior tibial slope increased from 9.4° to 11.7° (P < .05). Of the osteotomies, 3 (6%) were considered failures, defined by revision of the osteotomy or conversion to total knee arthroplasty. Performing proximal tibial opening wedge osteotomies to treat symptomatic medial compartment osteoarthritis in carefully selected patients leads to a significant improvement in subjective and objective clinical outcome scores with correction of malalignment at a mean of 3.6 years postoperatively. Level IV, therapeutic case series.