Context: There is abundant evidence that quality of life (QOL) is compromised in persons with multiple sclerosis (MS), but researchers have not yet examined the possible association between co-occurring symptoms and QOL in this population. Objectives: The objective of this study was to examine the symptom cluster of fatigue, pain, depression, and perceived cognitive complaints and its association with QOL in individuals with MS. Methods: The sample included 133 individuals with a definite diagnosis of MS who completed a battery of self-report measures as part of a cross-sectional study of symptoms and physical activity. The battery included the Fatigue Severity Scale, the Center for Epidemiological Studies-Depression Scale, the short form of the McGill Pain Questionnaire, the Perceived Deficits Questionnaire, and the Multiple Sclerosis Impact Scale. Results: Results indicated that 1) there were moderate bivariate correlations between fatigue, depression, pain, and perceived cognitive complaint scores; 2) the correlations between scores from the pairs of symptoms were attenuated when expressed as partial correlations controlling for the covariance of the remaining pair of symptoms; 3) exploratory and confirmatory factor analyses supported a single-factor model for the associations among fatigue, depression, pain, and perceived cognitive complaint scores; 4) cluster analysis identified three subgroups differing in experiences of fatigue, depression, pain, and perceived cognitive complaints; and 5) analysis of variance indicated a possible dose-response relationship between worsening symptoms and psychological and physical domains of QOL. Conclusion: Such findings provide emerging support for a dose-response relationship between worsening symptoms of fatigue, pain, depression, and perceived cognitive complaints and QOL in persons with MS. © 2010 U.S. Cancer Pain Relief Committee.