Evaluation of the relative contributions of generic and disease-targeted measures to assessing health-related quality of life (HRQOL) for chronic conditions is needed to help in selection of appropriate measures. We administered a generic HRQOL measure (the Short Form-36 [SF-36]), three disease-targeted supplemental scales to the SF-36, and two disease-targeted HRQOL instruments to 171 adults with multiple sclerosis. Most scales yielded adequate variability, internal consistency reliability, and test-retest reliability. The relationship between each measure and four primary "criterion" variables were assessed: overall symptom severity in the prior year; ambulation status; days unable to work or attend school in the prior month: and a rating of overall quality of life. Results indicate that the disease-targeted scales provided unique information not captured by the generic measure. We conclude that if a generic measure of HRQOL is desirable for a given study of multiple sclerosis, additional information will be gained by supplementing that measure with selected scales.