Our objective was to determine the frequency of antibodies to cyclic citrullinated peptides (CCPs) in a series of patients with a variety of rheumatic diseases. Seven hundred consecutive serum samples from patients at an outpatient clinic were tested for the presence of rheumatoid factor (RF) and anti-CCP. Clinical diagnosis, radiographic information, and other laboratory data were taken from patients' charts. The sensitivity and specificity of anti-CCP reactivity for the diagnosis of rheumatoid arthritis (RA) were 74.0% and 94.5%, respectively; the corresponding results for RF were 69.7% sensitivity and 81.0% specificity. Highest rates of false-positive RF tests were found in patients with SLE (18.3% vs. 12.7% CCP), Sjögren's syndrome (73.3% vs. 3.3% CCP), and a control group with chronic hepatitis (24.7% vs. 1.3% CCP). The detection of anti-CCP is useful for the diagnosis of RA because of its similar sensitivity but higher specificity compared with RF. Anti-CCP also helps to diagnose other inflammatory and noninflammatory diseases (especially connective tissue diseases) by reducing the rate of false-positive results in comparison with RF.