To determine whether the clinical and immunological expression of patients with cryoglobulinaemia associated with chronic hepatitis C virus (HCV) infection varied according to HCV-RNA load, HCV genotype or human immunodeficiency virus (HIV) coinfection. We studied 340 HCV patients (188 women and 152 men, with a mean age of 49 years) consecutively diagnosed with cryoglobulinaemia between 1993 and 2003 in our hospital. HCV infection was confirmed by serum HCV-RNA determination in all patients. Two hundred and forty-eight (73%) patients had asymptomatic cryoglobulinaemia and 92 (27%) presented cryoglobulinaemic symptoms. Patients with genotype 1 had a higher mean age at diagnosis of cryoglobulinaemia (48.2 vs 40.2 yrs, P < 0.001) and a higher prevalence of cryoglobulinaemic symptoms (25%vs 10%, P = 0.02), especially of vasculitic features (19%vs 5%, P = 0.014). In comparison with monoinfected HCV patients, those with HIV coinfection had a lower mean age at diagnosis of cryoglobulinaemia (40.4 vs 52.8 years, P < 0.001), a lower prevalence of cryoglobulinaemic symptoms (15%vs 34%, P < 0.001), vasculitis (10%vs 28%, P < 0.001), associated systemic autoimmune disease (3%vs 14%, P = 0.001), rheumatoid factor (30%vs 70%, P = 0.001) and hypocomplementaemia (50%vs 78%, P = 0.01). In HCV-HIV patients, a high viral load was associated with a high frequency of symptomatic cryoglobulinaemia, especially in patients with a high viral load of the two viruses (50%vs 7%, P = 0.001) A higher frequency of cryoglobulinaemic symptoms (especially vasculitis) was found in patients with HCV monoinfection and in those carrying HCV genotype 1. In contrast, patients with HIV coinfection presented a threefold lower prevalence of vasculitis. Associated HIV infection significantly attenuated the clinical and immunological expression of cryoglobulinaemia, except in coinfected patients with high viral loads for the two viruses.