Objective. Systemic sclerosis (SSc) is a complex, multisystem connective tissue disease in which genetic factors contribute to disease susceptibility. The aim of this study was to localize chromosome regions associated with susceptibility to SSc in a relatively isolated and homogenous population of Choctaw Indians with a high prevalence of SSc. Methods. A genome-wide microsatellite screen at 10 cM resolution (400 markers) was performed in 20 Choctaw patients with SSc and 76 ethnically matched controls. Based on the results of the initial screen, fine-scale microsatellite mapping at ≤1 cM resolution was performed in 10 selected chromosome regions. Allele and marker haplotype frequencies were compared between SSc patients and controls. Results. From the genome-wide screen, 12 markers showed evidence of highly significant associations with SSc in this population (P < 0.01), while 5 other markers showed significant associations (0.01 < P < 0.05). Among these markers, loci D5S410, D6S422, D15S978, and D20S107 are near the SPARC, MHC, FBN1, and TOPOI genes, respectively, confirming the results of our previous studies, which used different markers. D1S2800 and D14S63 have been reported to show linkage to systemic lupus erythematosus (SLE) in family-based studies, and DIS206, D6S422, and D6S264 are loci on 1p21.2, 6p22.3, and 6q23-27, respectively, which are in regions reported as showing linkage to SLE and other autoimmune diseases. Other markers showing unique associations with SSc were D7S510 (7p12-11), D7S661 (7q35), D8S514 (8q24.12), D19S221 (19p13.2), D19S220 (19q13.2), D22S423 (22q13.1), DXS1068 (Xp11.4), and DXS8055 (Xq21-23). Further analysis with fine-scale microsatellite mapping revealed at least 14 potential haplotypes associated with SSc. Conclusion. Our findings indicate that a number of genetic loci may contribute to the high prevalence of SSc in the Choctaw and are consistent with the paradigm that some autoimmune rheumatic diseases are likely to share genetic determinants.