The Schedule for the Evaluation of the Individual Quality of Life-Direct Weighting (SEIQoL-DW) has been used to measure quality of life (QoL) in small cohorts of individuals with ALS, but its suitability for assessing aggregate QoL for between-group comparisons is uncertain. We undertook a prospective study in which 120 patients with ALS completed two measures of QoL, the SEIQoL-DW and the McGill Quality of Life Single-Item Scale (MQoL-SIS). There was a weak correlation between the SEIQoL-DW index score and the MQoL-SIS. Only three of five cues accounted for a significant amount of variance in the MQoL-SIS, and even those accounted for only 12.8%-13.9% of the variance. Cues relating to family or significant other were chosen by over 90% of patients, and were the most heavily weighted. This study demonstrates that the SEIQoL-DW is of great value in identifying those factors which contribute to the psychosocial well-being of an individual with ALS. However, SEIQoL index scores may not reflect aggregate QoL of groups of patients with ALS, and may be measuring a construct other than QoL. Caution should be exercised in using the SEIQoL index score to measure QoL of groups, such as would be needed in interventional trials.