Background: Muscle damage has been found in patients with neuromyelitis optica spectrum disorder (NMOSD), but whether this damage is related to aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) is uncertain. The aim of this study was to investigate the relationship between AQP4-IgG and muscle damage. Methods: From January 2009 to May 2019, we prospectively screened 1209 Chinese Han patients with acute transverse myelitis (ATM). Ultimately, we included 203 ATM patients in the cohort study and compared log serum creatine kinase (sCK) levels between positive and negative AQP4-IgG statuses. Results: Among all ATM patients, the mean log sCK levels of AQP4-IgG-positive patients were higher than those of AQP4-IgG-negative patients (4.46 ± 0.10 vs. 4.16 ± 0.06, p < 0.001). In addition, among ATM patients diagnosed with NMOSD, the mean log sCK levels of AQP4-IgG-positive patients were higher than those of AQP4-IgG-negative patients (4.46 ± 0.10 vs. 4.05 ± 0.13, p = 0.025). The number of extremely high sCK values (sCK values > 300 IU/L) was significantly higher in ATM patients positive for AQP4-IgG than in those negative for AQP4-IgG (p = 0.020). Furthermore, multivariable linear regression model analysis showed that male sex (coefficient [95% CI] = 0.548 [0.286, 0.809], p < 0.001), serum AQP4-IgG (coefficient [95% CI] = 0.462 [0.237, 0.687], p < 0.001), and combined connective tissue disease (CTD) (coefficient [95% CI] = -0.686 [-1.145, -0.226], p = 0.004) were independent predictors of log sCK levels. Conclusions: Our study suggests that muscle damage in NMOSD patients may be associated with AQP4-IgG. © 2020 Elsevier B.V.