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Introduction Prior studies have demonstrated increased risk of cancer-associated scleroderma (CAS) in autoantibody subgroups, but data have been limited on tumor specificity, timing, and autoantibody type and breadth. We examined the risk of specific tumor types across the disease course in autoantibody and phenotype subsets.Material and Methods The SEER registry was used to compare cancer incidence between the Johns Hopkins scleroderma cohort (N=2769) and general US population. Eleven autoantibodies were assayed using EuroImmun (anti-centromere, topoisomerase 1, RNA polymerase III (POLR3), fibrillarin, NOR-90, Th/To, PM/Scl, Ku, Ro52), a commercial ELISA (anti-U1RNP), and a custom ELISA (anti-RNPC3). Standardized incidence ratios (SIR) for cancer were calculated for autoantibody/cutaneous subgroups within 3 years of (‘CAS’) and >3 years after (‘later’) scleroderma onset. Anti-POLR3-positive University of Pittsburgh patients (N=415) were analyzed to test whether there was attenuation of cancer risk when anti-RNA polymerase I antibodies were also present, as testing for anti-POLR3 and anti-POLR1 was systematically performed in this cohort.Results Anti-POLR3-positive Johns Hopkins patients had an increased risk of CAS (SIR 2.31, 95% CI 1.59-3.24), with high risks of breast (SIR 2.99, 95% CI 1.55-5.22), lung (SIR 3.74, 95% CI 1.21-8.72), tongue (SIR 23.02, 95% CI 2.79-83.17) and prostate cancer (SIR 4.55, 95% CI 1.48-10.62). Anti-POLR3-positive limited scleroderma patients had increased hematologic malignancy risk (SIR 10.29, 95% CI 1.25-37.18). Anti-POLR3-positive patients did not have elevated cancer risk beyond 3 years. Exploratory analyses suggested that anti-Ro52 associated with high CAS risk and anti-RNPC3 associated with increased early breast cancer risk. Late cancer incidence was decreased in anti-centromere-positive patients (SIR 0.65, 95% CI 0.47-0.88), especially for breast cancer (SIR 0.52, 95% CI 0.26-0.93), and in anti-Th/To-positive (SIR 0.46, 95% CI 0.20-0.91) and autoantibody negative (SIR 0.48, 95% CI 0.21-0.95) patients. In both cohorts, CAS risk was attenuated in anti-POLR3-positive patients with broader autoantibody responses. At Johns Hopkins, patients with anti-POLR3 alone had a significantly elevated risk of CAS (SIR 2.73, 95% CI 1.83-3.91), whereas those with anti-POLR3 and other autoantibodies did not have an increased risk (SIR 1.10, 95% CI 0.30-2.81). In the Pittsburgh cohort, there was an increased CAS risk in those who had only anti-POLR3 (SIR 2.51, 95% CI 1.34-4.29) but not in those who additionally had anti-POLR1 (SIR 0.67, 95% CI 0.29-1.33).Conclusions Anti-POLR3-positive scleroderma patients had increased risk of CAS for several tumor types, suggesting targeted cancer screening strategies should be studied. Risk was attenuated in those with additional autoantibodies and later in the disease.