Autoantibodies against interferon (IFN) can be found in patients with systemic lupus erythematosus (SLE). However, detailed information about the occurrence of type-specific antihuman IFN antibodies is not available. In this study, we investigated the incidence of autoantibodies specifically recognizing various type I IFNs (α1, α2, β, ω) and type II IFN (γ). Sera from 100 SLE patients were screened for the presence of IFN-binding antibodies by ELISA, using various types of recombinant IFNs as antigen. On the whole, autoantibodies against type I or type II or both IFNs were detected in 45% (45 of 100) of the serum samples investigated. More than half (56%) of the positive samples (25 of 45) contained antibodies specific only for type I IFNs, and 36% of positive sera (16 of 45) had autoantibodies only against type II IFN. Antibodies against both type I and type II IFNs were detected in 8% (4 of 45) of the positive samples. Among autoantibodies to type I IFNs, the most abundant were those against the type IFN-ω (15%) and the subtype IFN-α2 (11%). Autoantibodies binding subtype IFN-α1 and type IFN-β were detected at a relatively lower incidence of about 3%-4%. The highest occurrence (20%) showed autoantibodies to the proinflammatory cytokine, IFN-γ. We did not find any correlation between the production of autoantibodies against particular IFN species and an antibody response to other IFN species. We further observed that 84% (38 of 45) of the positive sera bound only one IFN species, and 13% (6 of 45) of positive samples contained antibodies against two IFN species of five different combinations (α1/β, α1/ω, α2/ω, α2/γ, ω/γ). One sample uniquely showed reactivity with three IFN species (α2/ω/γ). Our findings suggest that formation of autoantibodies could reflect humoral immune responses to increased spontaneous production of the respective IFN species in SLE patients.