Health-Related Quality of Life (HRQoL) research is gaining acceptance in the field of multiple sclerosis (MS). Little is known about what precipitates quality of life change. It was hypothesized that physical aspects of quality of life decline with worsening objective disease measures and psychosocial aspects remain relatively stable regardless of change in objective measures. These assumptions are tested using data from a Phase 3 study of relapsing-remitting MS patients treated with interferon beta-1a and reassessed approximately eight years after study initiation. The Sickness Impact Profile (SIP) questionnaire is the generic quality of life measure used in this study. Three summary scores of the SIP (Physical, Psychosocial, and Total scores), Expanded Disability Status Scores, Multiple Sclerosis Functional Composite, and Brain Parenchymal Fraction were determined at baseline, year 2, and after an average of 8.1 years from study entry. SIP data collected during a clinic visit were available from 137 of the original 172 participants. All objective indicators worsened by follow-up. SIP Physical and Total scores significantly worsened from baseline to follow-up. SIP Psychosocial showed nonsignificant worsening. Regression analysis indicated that final measures of SIP Physical and Total scores were most strongly associated with change in objective measures and follow-up SIP Psychosocial was most strongly related to earlier scores on the same measure.