The aim of our study was to evaluate the clinical and HLA-class II allele associations of some anti-cofactor antibodies in a homogeneous group of European patients with SLE. One hundred thirty-six patients with SLE, fulfilling four or more of the ACR 1997 revised criteria for the classification of the disease, coming from 7 European countries, were enrolled consecutively. Anti-prothrombin (anti-PT), anti-annexin V (anti-AnnV), anti-protein C (anti-Cprot) and anti-protein S (anti-Sprot) were determined by using commercial ELISA kits. Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1, DQB1 and DPB1 loci was performed by using PCR-SSOP method, carried out using digoxygenin (DIG) labeled probes. The prevalence of anti-AnnV, anti-PT, anti-Cprot and anti-Sprot was 19%, 10.4%, 4.4% and 8.1%, respectively. Twenty-seven % of anti-AnnV positive patients reported migraine vs 5.5% of anti-AnnV negatives (p = 0.003, but p not significant, odds ratio (OR) = 6.4, 95% confidence interval (CI) = 2-21). Anti-PT, anti-AnnV and anti-Sprot were positively associated with some HLA alleles, but pc was not significant. In this study we have shown that some HLA alleles carry the risk to produce antibodies against phospholipid-binding proteins, but these association need confirmation in other studies, because they have never been reported and appear to be weak associations.