To determine the prevalence of hepatitis C virus (HCV) infection in patients with sicca syndrome, and to determine the clinical, immunologic, and genetic characteristics of sicca syndrome associated with HCV. We conducted a prospective study in a university hospital immunology-rheumatology department. Sixty-two consecutive patients with sicca syndrome according to the European criteria for Sjögren's syndrome were included. HCV infection was diagnosed in patients with positive recombinant immunoblot assay findings and the presence of viral RNA in serum and saliva. Rheumatoid factor (RF), cryoglobulins, antinuclear antibodies, and anti-SS-A/SS-B antibodies were sought. HLA typing was performed on all patients. The prevalence of HCV infection in patients with sicca syndrome was 19%. The incidence of neurologic involvement was significantly increased in patients with sicca syndrome associated with HCV infection (24% versus 4%; P < 0.03), as was elevations in transaminase levels (87.5% versus 16%; P < 0.0001). RF and cryoglobulins were more frequent in HCV-positive sicca syndrome patients (62% versus 30%; P < 0.03, and 56% versus 10%; P < 0.001, respectively). In contrast, anti-SS-A/SS-B antibodies were present in 38% of HCV-negative sicca syndrome patients, but in only 1 HCV-positive sicca syndrome patient (P < 0.01). No significant difference in HLA type was observed. Viral RNA was present in the saliva of 83% of HCV-positive sicca syndrome patients, but in none of the HCV-negative sicca syndrome patients. We observed a high prevalence of HCV infection in our patients with sicca syndrome. HCV-positive sicca syndrome patients had specific clinical characteristics and were seronegative for SS-A/SS-B antibodies. Moreover, HCV RNA was present in the saliva of patients with HCV-associated sicca syndrome.