ABSTRACT: This study examined the symptom cluster of fatigue, pain, and depression as a correlate of reduced quality of life (QOL) in individuals with multiple sclerosis (MS). The sample included 291 individuals with a definite diagnosis of MS who were enrolled in a 6-month longitudinal study of physical activity and QOL. The participants completed baseline measures of fatigue, depression, and pain and follow-up measures of QOL. Cluster analysis initially identified three subgroups differing in experiences of fatigue, depression, and pain, and analysis of variance then indicated that the three subgroups differed in QOL. The subgroup with lowest scores on all three symptoms had the highest QOL, whereas the subgroup with the highest scores on the symptoms had the worst QOL. Such findings provide preliminary support for fatigue, pain, and depression as a symptom cluster that correlates with reduced QOL in persons with MS.