Objective: Pain is common in older adults and typically involves multiple sites. Obesity is an important risk factor in the pathogenesis of pain and multisite pain (MSP). This study aimed to examine longitudinal associations between fat mass and MSP, and to explore the potential mechanisms of any associations. Methods: Data from a longitudinal population-based study of older adults (n = 1,099) were utilized with measurements at baseline and after 2.6 and 5.1 years. At each time point, presence/absence of pain at the neck, back, hands, shoulders, hips, knees, and feet was assessed by questionnaire. Fat mass was assessed by dual x-ray absorptiometry, and height and weight were measured. Results: Participants were of mean age 63 years, mean body mass index (BMI) 27.9 kg/m2, and 51% women. Participants reporting greater number of painful sites had greater fat mass, fat mass index (FMI), and BMI both cross-sectionally and longitudinally. In multivariable analyses, fat mass was associated with MSP (odds ratio [OR] 1.06 per SD; 95% confidence interval [95% CI] 1.02–1.10) and pain at the hands, knees, hips, and feet (OR 1.29–1.99 per SD, P < 0.05 for all). Results were similar for FMI and BMI, although the latter was also associated with back pain (OR 1.25 per SD, 95% CI 1.02–1.54). Conclusion: Fat mass, FMI, and BMI are associated with MSP and pain at all lower-extremity sites and hand pain, independent of sociodemographic, physical activity, and psychological factors. This suggests that both loading and systemic inflammatory factors may have an important role in the pathogenesis of fat-related MSP.