In scleroderma patients, isolated pulmonary hypertension (PHT) has been associated with selected HLA haplotypes, severe impairment of the diffusing capacity for carbon monoxide and the diagnosis of CREST. Most patients with CREST have a late-age onset of the disease, corresponding to the perimenopausal or postmenopausal period. We conducted a retrospective cohort study to determine the role of post-menopause and of the other known clinical and biological markers in the development of isolated pulmonary hypertension in Italian patients with systemic sclerosis. 189 female patients with scleroderma who had no ecographic signs of pulmonary hypertension (PHT) and radiographic signs of lung fibrosis at the first visit and did not develop significant pulmonary fibrosis during the observation time were included. Sixty-three out of 189 patients (33.3%) presented isolated pulmonary hypertension. A severe impairment of diffusing capacity for carbon monoxide at admission was found to be an early predictive element for its development. An increased risk was associated with postmenopausal condition (RR = 5.2, p = 0.000), CREST syndrome (RR = 2.8, p = 0.001) and haplotype HLA-B35 (RR = 2.8; p = 0.002). A significant positive interaction between postmenopausal condition and either HLA-B35 (RR = 15.2; p = 0.000) or the diagnosis of CREST (RR = 14.1; p = 0.000) was found. Postmenopausal condition alone or in combination with HLA-B35 and CREST syndrome is the main risk-factor for developing primary pulmonary hypertension in scleroderma patients. This suggests that hormonal replacement therapy could play a role in preventing isolated PHT in patients with systemic sclerosis.