OBJECTIVES To determine whether decreases in exercise 1) were greater in individuals who were diagnosed as having hypercholesterolemia than in those without the diagnosis during follow-up and 2) were greater in incident hypercholesterolemic participants starting statins than in those not treated with cholesterol-lowering medications. PARTICIPANTS AND METHODS Regression analyses of changes since baseline (Δ) in exercise vs diagnosis of hypercholesterolemia and its treatment in 66,377 runners and 12,031 walkers not using cholesterol medications at baseline who were resurveyed during the National Runners' and Walkers' Health Study follow-up (January 1, 1991, through December 31, 2006). RESULTS A total of 3510 runners began statin treatment, 1779 began other or unspecified cholesterol-lowering drug treatment, and 2583 had untreated hypercholesterolemia; 58,505 runners remained nonhypercholesterolemic controls during the mean 7.2-year follow-up. Usual distance run decreased significantly more in hypercholesterolemic runners who began taking statins (mean ± SE: -0.47±0.06 km/d) than in runners who remained nonhypercholesterolemic during follow-up (-0.08±0.02 km/d) (P<.001). However, running distance also decreased significantly more in hypercholesterolemic runners who began unspecified/other (-0.52±0.08 km/d) or no (-0.47±0.07 km/d) cholesterol drugs than in nonhypercholesterolemic runners during follow-up. Moreover, Δrunning distance did not differ significantly between hypercholesterolemic runners who were statin treated vs those treated with other/unspecified (P=.64) or no (P=.94) cholesterol drugs. Initiating statin therapy was not associated with Δrunning pace in hypercholesterolemic runners or Δwalking distances in hypercholesterolemic walkers. CONCLUSION These results are consistent with the premise that a decrease in running distance is associated with hypercholesterolemia and do not suggest that statins reduce exercise level or intensity.