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Objective: This study aims to explore the frequency and influencing factors of asymptomatic spinal lesions (ASLs) and their impact on subsequent relapses in patients with AQP4‐IgG‐positive NMOSD (AQP4‐NMOSD) in a real‐world setting. Methods: We retrospectively reviewed clinical information and spinal MRI data from AQP4‐NMOSD patients who had at least one spinal cord MRI during their follow‐ups. Kaplan–Meier curves and Cox proportional hazards models were employed to ascertain potential predictors of remission ASLs and to investigate factors associated with subsequent relapses. Results: In this study, we included 129 patients with AQP4‐NMOSD and reviewed 173 spinal MRIs during attacks and 89 spinal MRIs during remission. Among these, 6 ASLs (3.5%) were identified during acute attacks, while 8 ASLs (9%) were found during remission. Remission ASLs were linked to the use of immunosuppressive agents, particularly conventional ones, whereas no patients using rituximab developed ASLs (p = 0.005). Kaplan–Meier curve analysis indicated that patients with ASLs had a significantly higher relapse risk (HR = 4.658, 95% CI: 1.519–14.285, p = 0.007) compared to those without. Additionally, the use of mycophenolate mofetil (HR = 0.027, 95% CI: 0.003–0.260, p = 0.002) and rituximab (HR = 0.035, 95% CI: 0.006–0.203, p < 0.001) significantly reduced the relapse risk. However, after accounting for other factors, the presence of ASLs did not exhibit a significant impact on subsequent relapses (HR = 2.297, 95% CI: 0.652–8.085, p = 0.195). Interpretation: ASLs may be observed in patients with AQP4‐NMOSD. The presence of ASLs may signify an underlying inflammatory activity due to insufficient immunotherapy. The administration of immunosuppressive agents plays a key role in the presence of remission ASLs and the likelihood of subsequent relapses. [ABSTRACT FROM AUTHOR]