We studied the long term impact of running and other aerobic exercise on musculoskeletal pain in a cohort of healthy aging male and female seniors who had been followed for 14 years. We conducted a prospective, longitudinal study in 866 Runners' Association members (n = 492) and community controls (n = 374). Subjects were also categorized as Ever-Runners (n = 565) and Never-Runners (n = 301) to include runners who had stopped running. Pain was the primary outcome measure and was assessed in annual surveys on a double-anchored visual analogue scale (0 to 100; 0 = no pain). Baseline differences between Runners' Association members and community controls and between Ever-Runners versus Never-Runners were compared using chi-square and t-tests. Statistical adjustments for age, body mass index (BMI), gender, health behaviors, history of arthritis and comorbid conditions were performed using generalized estimating equations. Runner's Association members were younger (62 versus 65 years, p < 0.05), had a lower BMI (22.9 versus 24.2, p < 0.05), and less arthritis (35% versus 41%, p > 0.05) than community controls. Runners' Association members averaged far more exercise minutes per week (314 versus 123, p < 0.05) and miles run per week (26 versus 2, p < 0.05) and tended to report more fractures (53% versus 47%, p > 0.05) than controls. Ever-Runners were younger (62 versus 66 years, p < 0.05), had lower BMI (23.0 versus 24.3, p < 0.05), and less arthritis (35% versus 43%, p < 0.05) than Never-Runners. Ever-Runners averaged more exercise minutes per week (291 versus 120, p < 0.05) and miles run per week (23 versus 1, p < 0.05) and reported a few more fractures (52% versus 48%, p > 0.05) than Never-Runners. Exercise was associated with significantly lower pain scores over time in the Runners' Association group after adjusting for gender, baseline BMI, and study attrition (p < 0.01). Similar differences were observed for Ever-Runners versus Never-Runners. Consistent exercise patterns over the long term in physically active seniors are associated with about 25% less musculoskeletal pain than reported by more sedentary controls, either by calendar year or by cumulative area-under-the-curve pain over average ages of 62 to 76 years.