Background Neuromyelitis optica spectrum disorder (NMOSD), a relapsing autoimmune demyelinating disease of the CNS, often leads to severe visual and/or motor disability. This study aimed to evaluate the long-term effects of the first-line immunotherapies on relapse and disability, and identify the prognostic predictors in NMOSD. Methods In this prospective cohort study, we enrolled patients with NMOSD from Southwest China and performed a long-term follow-up. We compared no immunotherapies (NIT) versus treatment of mycophenolate mofetil (MMF), azathioprine (AZA), or only corticosteroid (CS). Cox proportional-hazards model was used to explore the prognostic predictors in NMOSD. Results Ultimately, 281 patients were enrolled during 2009 to 2017. The proportions of relapse, motor disability, and mortality were significantly lower in treatments of MMF and AZA than in NIT (all P < 0.001), while no significant difference was found between the CS and NIT groups. The multivariate Cox analyses indicated that onset with optic neuritis and increased age at onset were risk predictors of visual disability and motor disability, respectively. Comparing with NIT, MMF and AZA were remarkably reduced risk of relapse and motor disability but not visual disability. Additionally, median time to first relapse and motor disability was significantly longer in treatments of MMF and AZA than in NIT (both P < 0.001). Furthermore, we estimated the risk of relapse and disability for AQP4-Abs positive NMOSD in 1-5 years based on prognostic predictors identified above. Conclusions Our study revealed the potential predictors of relapse and disability, and strengthened evidence that early immunosuppressive treatments, such as MMF and AZA, could effectively reduce the risk of relapse and disability, and delayed progression of NMOSD.