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Creatine phosphokinase (CPK) estimations are done routinely in some HIV clinics, irrespective of patient symptoms. We studied patients attending the Worcestershire HIV clinic between 1987 and 2001 to identify whether routine elevations in serum levels of CPK in patients with HIV were associated with clinical features of muscle disease (CFMD), and whether such elevations influenced patient management. There was no association between CFMD and a rise in CPK. Major rises of CPK >400 IU/L were significantly associated with CFMD. No individual had a persistent CPK rise >200 IU/L without CFMD. In the great majority of cases, there was no change in management consequent to enzyme rises. In patients with HIV infection and no CFMD, the chance of finding a major and persistent CPK rise is low. This study does not support the practice of routine monitoring of CPK in asymptomatic patients attending HIV clinics.