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Objectives: We examined whether an array of scleroderma autoantibodies associates with risk of cancer and could be useful tools for risk stratification. Methods: Scleroderma cancer cases and scleroderma controls without cancer from the Johns Hopkins Scleroderma Center and the University of Pittsburgh Scleroderma Center were studied. Sera were assayed by Lineblot and enzyme‐linked immunosorbent assay (ELISA) for autoantibodies against centromere, topoisomerase 1, RNA polymerase (POLR) 3, PM/Scl, Th/To, NOR90, U3 RNP, Ku, Ro52, U1RNP, and RNPC3. Logistic regression models were constructed to examine whether distinct autoantibodies associated with overall cancer at any time and cancer‐associated scleroderma (cancer occurring three years before and after scleroderma onset). The effects of having more than one autoantibody on cancer were further examined using random forest analysis. Results: A total of 676 cases and 687 controls were studied. After adjusting for relevant covariates, anti‐POLR3 (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.03–2.11) and monospecific anti‐Ro52 (OR 2.19, 95% CI 1.29–3.74) were associated with an increased overall cancer risk, whereas anticentromere (OR 0.69, 95% CI 0.51–0.93) and anti‐U1RNP (OR 0.63, 95% CI 0.43–0.93) were associated with lower risk. When examining risk of cancer‐associated scleroderma, these immune responses remained associated with increased or decreased risk: anti‐POLR3 (OR 2.28, 95% CI 1.33–3.91), monospecific anti‐Ro52 (OR 2.58, 95% CI 1.05–6.30), anticentromere (OR 0.39, 95% CI 0.20–0.74), and anti‐U1RNP (OR 0.32, 95% CI 0.11–0.93). Anti‐Ro52 plus anti‐U1RNP or anti‐Th/To was associated with decreased cancer risk compared with anti‐Ro52 alone. Conclusions: These data suggest that five distinct scleroderma immune responses, alone or in combination, may be useful tools to stratify the risk of cancer for scleroderma patients. Further study examining cancer risk in autoantibody subgroups relative to the general population is warranted. [ABSTRACT FROM AUTHOR]