Objectives: Osteochondritis dissecans (OCD) is a condition characterized by abnormal subchondral bone with disturbance of overlying articular cartilage. Pathophysiology for the etiology and underlying mechanism of OCD lesion development is not fully understood. The purpose of this study was to determine the association of lower extremity weightbearing axis with femoral condyle OCD lesion location, and if this association was affected by certain patient and OCD lesion characteristics such as lesion stability, skeletal maturity, and the presence of the OCD lesion on the medial versus lateral femoral condyle. Methods: This was a retrospective case series at a single, large academic institution. The primary outcome was the association of femoral condyle OCD lesion location with lower extremity weightbearing axis as categorized by Cahill and Berg zones of the knee. Secondary outcomes included sub-group analyses (treatment, skeletal maturity, and lesion stability) and contribution of femoral and tibial mechanical axis to lower extremity weightbearing axis deviations (mechanical lateral distal femoral angle [mLDFA] and medial proximal tibial angle [MPTA]). For unilateral OCD lesions, mechanical axis was compared between affected and unaffected lower extremities. Results: Eighty-six patients and 95 knees with an OCD lesion of the femoral condyle were identified, with 9 patients (11%) having bilateral OCD lesions. There were 74% male patients with average age of 21 years old. 65% of knees had closed distal femoral physes, 82% of OCD lesions were unstable on MRI imaging, and 85% underwent a surgical procedure. Seventy-five percent of OCD lesions were located in Cahill and Berg zone 2 at the lateral aspect of the medial femoral condyle. Lower extremity mechanical axis was located in the same zone as the OCD lesion in 48% of cases and within the same knee compartment in 56% of cases. Over 90% of OCD lesions were within ±1 zone of the weightbearing axis. There were no significant differences in the association of mechanical axis and OCD lesion location in subgroup analysis of medial versus lateral femoral condyle OCD lesions, skeletal maturity, stability of the lesion, or treatment group. For patients with varus alignment and medial femoral condyle OCD lesions, the mean mLDFA was 89.9° and MPTA was 85.4°, whereas for valgus alignment and lateral femoral condyle lesions, the mLDFA was 84.8° and MPTA was 88.8°. Both the mLDFA and MPTA were significantly different when comparing medial to lateral femoral condyle OCD lesions (p <0.001 and <0.001, respectively). Patients with unilateral medial femoral condyle OCD lesions were more likely to have varus alignment of the affected extremity compared to the contralateral extremity (59% vs. 36%, p = 0.01). Conclusions: This study demonstrated a relationship between lower extremity mechanical weightbearing axis and femoral condyle OCD location. Patients with unilateral medial femoral condyle OCD lesions are more likely to have varus alignment in the affected extremity. Varus alignment associated with medial femoral condyle lesions had similar varus contributions from both femoral and tibial alignment whereas valgus alignment in the setting of lateral femoral condyle lesions appear to have predominantly femoral contributions. There were no significant differences in association with mechanical axis among medial versus lateral femoral condyle lesions, OCD lesion stability, or distal femoral physeal status. More work is required to better understand the relationship between mechanical axis and femoral condyle OCD lesion pathophysiology with the long-term goal of identifying patients at risk for progression of lesion instability and developing potential interventions to preserve articular cartilage.