Objective. Chronic hepatitis C virus (HCV) infection is associated with an array of autoimmune laboratory and clinical manifestations. The goals of our study were to identify host and/or virological factors that are implicated in the pathogenesis of these manifestations. Methods. We performed a detailed prospective study of various demographic, virological, biochemical, immunological (including lymphocyte subsets, Fcγ-receptor and HLA class-II genotyping), histological and host genetic parameters in 3 well defined subgroups of HCV patients (n = 40): patients with liver disease only (group I, n = 11) or with laboratory (group II, n = 20) and clinical (group III, n = 9) autoimmune manifestations. Results. Group III patients, mainly with features of mixed cryoglobulinemia, were older with higher levels of rheumatoid factor and circulating cryoglobulins while they tended to have a longer estimated disease duration compared to the other two groups of patients. We did not identify any specific immunological features that could differentiate symptomatic versus asymptomatic patients, except from the elevated soluble interleukin-2 receptor levels. An increased frequency of the R/R131 FcRγIIIA and the NA1/NA1 FcγRIIIB genotypes was observed in our total HCV population, regardless of autoimmune manifestations, compared to historical controls. No statistically significant differences in HLA class II allele frequencies was detected between patient subgroups or in comparison to healthy controls. Conclusions. Chronically infected HCV patients with symptomatic mixed cryoglobulinemia display a number of unique characteristics that differentiate them from asymptomatic patients with chronic hepatitis C.