OBJECTIVES: To assess the change in general health-related quality of life (HRQoL) of multiple sclerosis (MS) patients after one year of natalizumab treatment in the usual care setting.  METHODS: MS patients, newly initiating natalizumab, were recruited to participate in a longitudinal observational study to assess general HRQoL using the SF-12v2 prior to natalizumab initiation (baseline, BL) and after the 3rd, 6th and 12th infusions. Higher physical component summary scores (PCS) and mental component summary scores (MCS) on the SF-12v2 indicate better HRQoL.  Statistical regression models were used to evaluate changes in PCS and MCS scores from BL through the 12th infusion after controlling for BL covariates such as age, years since MS diagnosis, number of natalizumab infusions received, disability and functional status, number of MS drugs used prior to natalizumab and comorbidity burden. RESULTS: Data for 324 patients who completed the baseline through 12th infusion assessments are reported. The mean age was 46.5 (SD=10.4) and the majority of patients were female (77.8%). The mean number of years since MS diagnosis was 10.16 (SD=8.23). The adjusted PCS score improved significantly from baseline (BL 34.25, 12th infusion 36.66; p<0.001); similar significant improvements were observed in the adjusted MCS scores (BL 43.13, 12th infusion 46.77; p<0.001).  CONCLUSIONS: Patients reported improvements in general HRQoL measures after one year of natalizumab treatment in the usual care setting. These results are consistent with results from pivotal clinical trials and document the beneficial impact of natalizumab on HRQoL in MS patients.