Objective: This nationwide study aimed to investigate the association between newly diagnosed systemic sclerosis (SSc) and previous appendicitis history. Methods: A total of 1595 patients who were newly diagnosed with SSc were recruited as the SSc cases from the 2003 to 2012 claims data of the entire population in Taiwan. The other 15,950 individuals who had never been diagnosed with SSc during 2003 and 2012 were selected as the non-SSc controls to match the SSc cases. We defined that the index date as the first date of SSc diagnosis of SSc cases and the first date of ambulatory visit for any reason of non-SSc controls. Conditional logistic regression analysis was applied for the association between appendicitis and the risk of the incident SSc, tested by estimating odds ratios (ORs) with 95% confidence intervals (CIs). Potential confounders, including the Charlson comorbidity index (CCI), a history of periodontal disease, salmonella infection, and intestinal infection, were controlled. We further designed sensitivity analyses by varying the definition of appendicitis according to the status of receiving primary appendectomy. Results: The mean age was 51 years in the case and control groups. Females accounted for 77.5%. A total of 17 (1.1%) out of 1595 SSc cases and 81 (0.5%) out of 15,950 non-SSc controls had a history of appendicitis before the index date had a history of appendicitis. A significant association between appendicitis and the risk of SSc was confirmed (OR, 2.03; 95% CI, 1.14–3.60) after adjusting potential confounders. CCI ≥ 1 (OR, 8.48; 95% CI, 7.50–9.58) and periodontal disease (OR, 1.55; 95% CI, 1.39–1.74) were also significantly associated with the risk of SSc. The association between appendicitis and SSc risk remained robust using various definitions of appendicitis. Conclusion: Our study demonstrated appendicitis was associated with the incident SSc. CCI ≥ 1 and periodontal disease also contributed to the risk of developing SSc.