In vitro studies have shown promising results for balloon-guided inflation tibioplasty. It was our hypothesis that this technique may be safe and effective for use in depressed lateral tibial plateau fracture. We performed a prospective study of all patients suffering from a depressed lateral tibial plateau fracture, managed in our institution with inflation tibioplasty and a resorbable calcium phosphate bone substitute injection, between January 2012 and December 2013. Twenty patients, mean age 54.3 +/- 12. 8 years, suffering from a depressed lateral tibial plateau fracture (Schatzker type II and III) were included. We then aimed to evaluate at a minimum follow-up of one year: (1) the rate of complications, (2) the clinical outcome (Knee Injury and Osteoarthritis Outcome (KOO) and 12-Item Short Form Health Survey (SF-12) scores); and (3) the radiographic outcome (evaluated by CT-scan). No peri-operative complications occurred. In one patient, calcium phosphate substitute was found in the infrapatellar fat pad on post-operative radiography with no clinical or radiographic consequences at one year. At one year after surgery, the KOO subscores were: Pain 80 (range 64-93), other symptoms 81.3 (69-93), daily living activities 81.9 (46-99), sport 65.83 (20-100), and quality of life 67.04 (31-100). The SF-12 activity component was 40.4 (28.6-52.2) and SF-12 mental component 47.71 (28 - 67.1). The mean depressed step-off of the lateral joint decreased from 10.7 +/- 4.8 mm pre-operatively to 2.7 +/- 1.7 mm post-operatively (p < 0.0001). Our observations suggest that the use of balloon-guided inflation tibioplasty with injection of a resorbable bone substitute is safe, and results in a high rate of anatomic reduction and good clinical outcomes in patients with depressed tibial plateau fractures. Level of Evidence: Therapeutic Level IV.