Little information exists about caregivers of persons with multiple sclerosis (MS). Our aims were to describe the characteristics of a sample of caregivers of persons with MS, assess their perceived burden, health-related quality of life, and investigate factors influencing this burden. We studied 278 caregivers of persons with MS, recruited from a Spanish cross-sectional survey, measuring health-related quality of life by the 36-Item Short-Form Health Survey (SF-36) and burden by the Zarit Caregiver Burden Interview. Of the caregivers, 56.8% were female and their mean age was 50.1 +/- 12.6 years. Their main relationship with the person with MS was spouse/partner (52.9%) and son or daughter (25.9%). Caregiver General Health, Mental Health, Bodily Pain, and Role-emotional Functioning were the most affected dimensions on the SF-36. Multiple regression analysis showed that independent and significant predictors of burden were Role-emotional Functioning and Vitality dimensions SF-36 scores of caregivers, and the Expanded Disability Status Scale scores. The total adjusted variance explained by these variables (adjusted R(2)) was 0.512. Emotional factors and the disability of the person with MS were major predictors of burden. Psychological and social support should be considered to reduce caregiver burden.