Objectives: The objectives of this study are to understand the impact of natalizumab on cognition beyond two years of therapy and to investigate whether baseline characteristics are predictive of clinical response. Methods: This is a single-center, 24-month, observational study. Sixty-three patients treated with natalizumab were assessed prior to monthly infusions using a Cogstate battery and the SDMT. A linear mixed model was conducted with duration of natalizumab therapy as a between-subjects factor (<=2 or >2 years), assessment as a within-subjects factor, and MSSS as a covariate. Results: There were no statistically significant differences between the key demographic variables aside for the MSSS (p=.0074). No patient showed evidence of sustained cognitive deterioration over the 24 month period. Irrespective of time on natalizumab, significant improvements were observed at the group level in executive function, verbal memory and working memory, whereas processing speed and attention remained unchanged. Impaired cognition or any other baseline parameter did not influence the trajectory of cognitive change over 24 months. Conclusion: Our results suggest that natalizumab preserves cognitive function, including the ability to learn, for 4 years and beyond of continuous therapy. This occurs irrespective of baseline characteristics.