Amyotrophic lateral sclerosis (ALS) is a process that leads to the functional disability of the individual in a relatively short period of time, with a very important limitation of autonomy and affecting the quality of life. We wished to determine the economic burden (direct and indirect costs), as well as health-related quality of life (HRQoL) in patients with ALS in Spain. A cross-sectional study was carried out on 63 patients with ALS during 2004. A retrospective assessment of the use of resources was obtained through questionnaires completed by the patients and/or the patients' caregivers. The approach used was a cost-of-illness study based on a societal perspective. We assessed the HRQoL with the EQ-5D. Mean annual cost per patient with ALS was euro36,194. The most important categories of costs were informal care, early retirement, medications, and orthopaedic devices. The mean EQ-5D index score was 0.18 and the mean EQ-5D VAS score was 29. Considerations of the costs related to caregiving to cope with the patients' disabilities, as well as the high indirect costs resulting from early retirement in patients with ALS, should become a priority for health authorities in Spain. The patients' HRQoL was very low and substantially influenced by the degree of severity of ALS.