We have previously detected autoantibodies against topoisomerase II alpha (anti-topo II alpha) in sera from patients with idiopathic pulmonary fibrosis. To determine whether anti-topo II alpha is also present in systemic sclerosis (SSc) patients with pulmonary involvement, we screened sera from 92 patients and 34 healthy controls. Presence of anti-topo II alpha was investigated with respect to clinical and serological features, including the frequencies of HLA class I and II alleles. Anti-topo II alpha was detected in 20/92 (21.7%) patients. No association was found with either anti-topoisomerase I (Scl-70 or anti-topo I) or anti-centromere antibodies. However, anti-topo II alpha was associated with the presence of pulmonary hypertension (PHT) (as opposed to pulmonary fibrosis), and with a decrease of carbon monoxide diffusing capacity. Anti-topo II alpha was strongly associated with the presence of the class I antigen HLA-B35. No significant association was found with HLA class II antigens. HLA-B35 also turned out to be associated with the presence of PHT. These results indicate that in SSc patients, the presence of anti-topo II alpha is associated with PHT, and that the simultaneous presence of HLA-B35 seems to add to the risk of developing PHT.