OBJECTIVE To investigate correlations between serum levels of topoisomerase I-specific antibody (anti-topo I) and clinical features of systemic sclerosis (SSc), including disease severity (the total skin score [TSS]) and disease activity. METHODS Using highly sensitive enzyme-linked immunosorbent assays, we measured the levels of anti-topo I antibody, including total IgG, individual IgG subclasses, and IgA, and analyzed their correlations with the TSS in 59 patients with SSc, all of whom had diffuse cutaneous involvement. Serial serum samples were obtained from 11 of these patients. RESULTS The titers of anti-topo I antibody, including IgG and IgA, were positively correlated with the TSS, a measure of SSc disease severity. In 8 of the 11 patients from whom serial serum samples were obtained, changes in the levels of both IgG and IgA, when detectable, paralleled changes in the TSS. In 3 patients, an increasing anti-topo I IgG level preceded an increase in the TSS. The level of each IgG subclass also correlated with and tended to parallel the TSS. The patients with very active disease had higher mean IgG (P < 0.001) and IgA (P < 0.05) titers than did those with inactive disease. CONCLUSION Serum levels of anti-topo I antibody correlate positively with disease severity and disease activity in SSc.