Introduction: High tibial medial open-wedge valgus osteotomy (HTO) is a well-established procedure for unicompartimental medial osteoarthritis of the young and active patient. However, the influence of cartilage defects of the lateral compartment on the total outcome remains obscure.Methods: From 2005 to 2012, a total of 63 patients underwent HTO for medial osteoarthritis of the knee at a single university orthopaedic center. Baseline data as well as intraoperative findings, including the grade and location of cartilage lesions, were evaluated retrospectively. Two groups were formed regarding the integrity of the lateral tibiofemoral compartment as measured by the Outerbridge score (group A: no lateral cartilage defects, group B: mild to moderate lateral cartilage defects). Functional outcome was assessed using the Knee and Osteoarthritis Outcome Score (KOOS), including its five subscores.Results: Comparing pre- and postoperative data, we identified an overall benefit of the HTO procedure as measured by the KOOS. Group A (no lateral cartilage defects) showed an increase in all five KOOS subscores (p = 0.00–0.01), whereas for group B (mild to moderate lateral cartilage defects), only two KOOS subscores revealed a significant increase (p = 0.03–0.04). There was also a statistically significant difference in the total KOOS score with higher values for group A at the postoperative visit. Cartilage defects with a higher Outerbridge score were associated with lower postoperative KOOS subscores.Discussion: Mild to moderate cartilage defects of the lateral compartment humble the total outcome after HTO procedure. Thus, indication for HTO should be made very carefully if any degree of lateral cartilage degeneration is present.