Objective <p>Nonuniform settlement of C2 lateral mass (C2LM-NUS) was defined as an asymmetrical change of the bilateral C2 lateral masses. This study aimed to determine the association between the nonuniform settlement of C2 lateral mass (C2LM-NUS) and lateral atlantoaxial osteoarthritis (AAOA).</p> Methods <p>A total of 573 patients who underwent a head and neck or cervical spine CT scan were reviewed. The morphological parameters were measured, including C2 lateral mass settlement (C2LMS), lateral atlantodental interval (LADI), coronal deviation angle of odontoid process (Od-CDA), and C1/2 relative rotation angle (C1/2 RRA). The lateral AAOA was recorded. The patients with a difference in C2LMS between the bilateral sides (d-C2LMS) of more than 1.4&#xa0;mm were assigned to the C2LM-NUS group.</p> Results <p>There were 154 patients in the C2LM-NUS group and 419 in the control group. The median values of the difference in LADI between the two sides (d-LADI), Od-CDA, and C1/2 RRA in the C2LM-NUS group were greater than those in the control group (<i>p</i> &lt; .001 for all). The prevalence of lateral AAOA in patients with C2LM-NUS was higher than in the control group (33.8% vs 19.1%, <i>p</i> &lt; .001). Multivariate logistic regression analysis revealed that the C2LM-NUS was an independent risk factor for lateral AAOA (Adjusted Odds Ratio: 2.382, <i>p</i> &lt; .001).</p> Conclusion <p>This study indicated that the C2LM-NUS, an independent anatomical risk factor for lateral AAOA, was associated with asymmetric morphological changes of the AAJ.</p>