Survivorship of unicondylar knee arthroplasty (UKA) remains a drawback, especially compared with the outcome of total knee arthroplasty. This could be improved by identifying and correcting failure mechanisms. To this purpose, this study aimed at exploring failure modalities of UKA, with particular focus on the role of joint line (JL) position and alignment as variable to be optimized for a successful outcome. This study explored modes of failure in 266 medial UKAs. Radiological comparison was performed between 24 failures and 24 matched controls, to determine the importance of UKA positioning in terms of femorotibial angle (FTA), tibial plateau angle, and posterior tibial slope (PTS). Radiographic comparative analysis showed statistically significant differences in the failure group compared with the control group in terms of variation in FTA ( = 0.0222), PTS ( = 0.0025), and JL height ( = 0.0022). Variations not only in FTA but also PTS and JL height were correlated with failures observed in this series. Thus, based on the results of this study, it emerges that JL position should be carefully controlled in all planes while implanting a UKA. This is a Level III, case-control study.