We have previously shown that the 90 kDa heat-shock protein (hsp90) is notably elevated in lupus patients with active neuro-psychiatric (NP) and/or cardio-respiratory (CR) disease. This elevation is dependent upon enhanced transcription of the hsp90 beta gene. Serial studies have shown that changes in hsp90 levels have a high level of sensitivity for changes in activity of NP, CR, haematological and renal SLE. We now present evidence that overexpression of hsp90 in lupus patients is associated with the presence of the anti-phospholipid syndrome, and with the absence of the HLA allo-/haplotypes most commonly found in this particular cohort of patients. We conclude that the upregulation of hsp90 expression in SLE has a genetic basis, and that this may be directly involved in pathogenesis in subsets of patients with this disease.