Hypoxia may play an important role in the pathogenesis of systemic sclerosis (SSc). Carbonic anhydrase IX (CA IX) is one of the hypoxia markers and its extracellular domain can be released into the serum. However, the clinical significance of serum CA IX levels in SSc is still unknown. The aim of this study is to evaluate the possibility that serum CA IX levels can be a specific disease marker of SSc. Serum samples were obtained from SSc patients and healthy controls. Patients diagnosed as scleroderma spectrum disorder (SSD), who did not fulfill the ACR criteria of SSc but were thought that they might develop SSc in the future, were also included in this study. Serum CA IX levels were measured with specific enzyme-linked immunosorbent assays. SSD patients had significantly lower CA IX levels than diffuse cutaneous SSc (dcSSc), limited cuntaneous SSc (lcSSc) and healthy control groups. Also, we found a significant decrease in the values in dcSSc patients compared to those of lcSSc patients. Serum levels of CA IX may be useful for the differentiation of lcSSc from SSD. Decreased serum CA IX levels in spite of the presence of hypoxia in SSc may indicate an impaired response to hypoxia, which leads to the persistent hypoxic condition. Our results suggest that the abnormal response to hypoxia may already exist in SSD patients, and may be involved in its pathogenesis.