This study aims to investigate the association of the presence and of the titer of autoantibodies against cyclic citrullinated peptides (aCCP), with clinical manifestations and disease activity in a cohort of patients with rheumatoid arthritis (RA). From January 2000 through December 2005, 135 patients were diagnosed with RA at the Rheumatology Unit of our hospital. Demographic, clinical, laboratory, and therapeutic parameters were evaluated in all patients at study entry and at every follow-up visit. Positivity in aCCP and also their levels were determined for all patients. At the end of the study, we reevaluated the above parameters, dividing patients into aCCP positive and aCCP negative. From 135 patients, 53.3% were aCCP positive. The majority of aCCP-positive patients were males (p<0.001), positive to rheumatoid factor (p<0.001) and current smokers (p<0.05). At diagnosis, aCCP-positive patients presented with higher tender joint counts (p<0.001) and swollen joint counts (p<0.001), and exhibited more active disease, expressed by higher disease activity scores for 28 joints (DAS-28) (p<0.001). At the end of the study, aCCP-positive patients also displayed more active disease, with higher DAS-28 (p<0.001), and more severe disease, as this was indicated by the higher radiological Larsen score (p<0.001). The serum levels of aCCP were not found to be associated with disease activity and severity. In early RA, the presence of aCCP is associated with increased disease activity and severity. This was found to be independent of circulating levels of aCCP.