OBJECTIVES: To assess change in health-related quality of life (HRQoL) over time in MS patients treated with natalizumab in a “usual care setting” in the United States (US). METHODS: MS patients starting natalizumab were invited to participate in a 1-year longitudinal health outcomes study assessing their experiences with natalizumab.  MS patients complete self-reported assessments prior to natalizumab initiation and after the 3rd, 6th and 12th natalizumab infusions. The current analysis reports the change in general HRQoL assessments using the SF-12v2 from baseline through the 6th natalizumab infusion. Physical and Mental Component Summary (PCS and MCS, respectively) scores were computed at each assessment. PCS and MCS scores range from 0 to 100, with higher scores indicating better HRQoL. The a-priori study hypothesis was that patient-reported HRQoL improves over time with longer duration of natalizumab treatment. Statistical regression models were used to evaluate changes in HRQoL over time after controlling for the number of natalizumab infusions, age, years since MS diagnosis, baseline disease disability and functional status, comorbidity burden, and number of drugs used prior to natalizumab. RESULTS: Data for 296 patients were analyzed. The mean age was 47+/-11 years and the majority of patients were female (78%). The mean number of years since MS diagnosis was 11+/-9 years. After controlling for covariates, a statistically significant increase (improvement) in PCS scores (BL 34+/-11, 3rd 36+/-12 and 6th 36+/-11; p<0.0001) and MCS scores (BL 43+/-12, 3rd 47+/-11 and 6th 48+/-11; p<0.0001) was observed from baseline through the 6th infusion.  CONCLUSIONS: Patients reported significant improvements in both physical and mental aspects of HRQoL over 6 months of treatment, suggesting an improved effect of natalizumab over time. These results document the improvement in HRQoL of MS patients receiving natalizumab in the usual care setting and are consistent with clinical study findings.