To evaluate the frequency of myopathy and serum creatine kinase (CK) elevation associated with the use of the integrase inhibitor raltegravir we conducted a retrospective, cohort analysis assessing the incidence of skeletal muscle toxicity among HIV-infected patients treated with raltegravir. Adult HIV-infected patients who started a raltegravir-containing therapy were enrolled into the study. The skeletal muscle toxicity was defined by the presence of one or more of the following parameters: (1) isolated and significant CK elevation without signs or symptoms; (2) diffuse myalgia without weakness; (3) proximal muscle weakness; (4) rhabdomyolysis. On the whole, 155 patients were included in the study, with a mean age of 49.2 years; the median duration of the raltegravir treatment was 30.7 months. The overall frequency of skeletal muscle toxicity was 23.9%, with an incidence of 4.7/100 person-years. An isolated CK elevation was reported in 21.3% of cases, while less than 3% of patients complained of myalgia or muscle weakness. The CK elevation was usually of grade 1 or 2 and self-limiting, and laboratory or clinical abnormalities did not require discontinuation of raltegravir in any patient. Factors significantly associated with skeletal muscle toxicity were previous use of zidovudine, higher baseline CK levels, previous increase of the CK levels, and a higher body mass index. Skeletal muscle toxicity is not an unusual adverse event in subjects receiving raltegravir, but it is usually represented by a mild-to-moderate increase in CK concentration, while clinical symptoms of myopathy are very uncommon.