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Systemic sclerosis (SSc) is a multisystem autoimmune disease of connective tissue characterized by immune dysregulation, obliterative vasculopathy, and fibrosis of skin and internal organs (1–3). Using microarrays, 4 previous studies have investigated the transcript profiles of SSc peripheral blood (PB) cells or their subpopulations. We first reported that, compared with PB cells from controls, PB cells from patients with early SSc have a distinct transcript pattern that includes dysregulation of interferon (IFN)–inducible genes (4). This observation was replicated by other investigators in PB mononuclear cells (PBMCs) (5), monocytes, and CD4+ T cells (6) and PB cells (7) from SSc patients. None of those studies found a correlation between the IFN signature and the clinical or serologic subtypes of SSc. Due to the heterogeneity of SSc, those studies may not have been sufficiently powered to assess subtle clinical and serologic differences in the transcript profile. However, Bos et al (7) reported that the expression levels of 5 IFN-inducible gene transcripts measured by quantitative polymerase chain reaction (PCR) in an extended group of 43 SSc patients were higher in patients without anticentromere antibodies (ACAs). Several studies have shown a striking pattern of up-regulated type I IFN–inducible genes in PBMCs from patients with systemic lupus erythematosus (SLE) (8–10). In particular, the presence of anti-Ro, anti–U1 RNP, anti-Sm, and anti–double-stranded DNA (anti-dsDNA) is significantly associated with a high IFN score in SLE (11). SSc shares several similarities with SLE, such as autoantibodies directed against nuclear antigens, and in some patients, overlapping clinical features. At the gene level, there is emerging evidence that SSc and SLE share common genetic associations, such as IRF5 (12–14) and PTPN22 (15–17). The risk alleles of the IRF5 and PTPN22 genes have been linked to higher serum levels of IFNα in SLE patients (18,19). Despite the evidence of similarities between SSc and SLE, a direct comparison of the transcript profiles of patients with the 2 diseases has not been undertaken. We now report the results of such a comparative study of a large number of SSc patients with SLE patients and controls. We analyzed our results using conventional methods and a newly described modular analysis framework (10). We examined whether SSc patients with certain genetic, clinical, or serologic features are more likely to have a transcript profile that is similar to that of SLE. The results place a subset of SSc patients alongside SLE in the continuum of IFN-mediated autoimmune diseases.