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Objective: The purpose of this study is to describe the MRI findings and treatment decisions and outcome for Morel-Lavallée lesions (MLLs) of the knee and to investigate whether evidence exists to support an increased frequency of such lesions on the medial or lateral side by performing a cadaveric experiment., Materials and Methods: In a 4-year period, 24 MRI studies of 24 consecutive patients (16 male patients and eight female patients) with knee MLLs were retrospectively reviewed. Patient demographic characteristics, treatment decisions and outcome, and associated injuries were recorded. The location of the MLL was categorized as medial, lateral, or global. Lesions were categorized according to an established MRI classification. During the cadaveric experiment, the compartmental pressures of the medial or lateral aspect of the knee were monitored in 20 cadaveric knees. The chi-square test, t test, and Pearson correlation were used for statistical analysis., Results: MLLs were located medially in 16 patients, laterally in two patients, and globally in six patients. The medial location was significantly more common than a lateral or global location (p < 0.05). MLLs were classified as type I in 14 patients, type II in eight patients, and type III in two patients. MRI type was correlated with the chronicity of injury (r 2 = 0.614; p = 0.0014). Fractures were the most common associated injuries, occurring in seven of 24 patients. In 17 patients, all of whom had conservatively treated type I or type II lesions, complete resolution of the MLL occurred. The maximum compartmental pressures were significantly higher on the lateral side than on the medial side (p < 0.0001)., Conclusion: Knee MLLs have a predilection for the medial side, which may be attributed to the lower resistance in this location, and they have variable patterns on MRI, which correlate with chronicity. Conservative treatment of type I and II lesions seems effective.