To evaluate the association of anti-IFI16 antibodies with peripheral vasculopathy and the predictive value of anti-IFI16 antibodies for the development or persistence of digital ulcers (DPDU) in SSc. A total of 42 SSc patients and 42 age- and sex-matched healthy controls were enrolled. Anti-IFI16 antibodies were examined by ELISA. Nailfold videocapillaroscopy (NVC) and power Doppler ultrasound (PDUS) were used to assess the micro- and macro-vascular involvement in SSc. All patients were followed up for 6 months to evaluate DPDU. Potential risk factors for DPDU were analyzed by a Firth's penalized logistic regression model. Of the 42 SSc patients enrolled, 19.05% patients were positive for anti-IFI16 antibodies, compared to a significantly low positivity rate of 4.76% in healthy controls (p < 0.001). SSc patients who were positive for anti-IFI16 antibodies manifested higher ulnar artery resistance index than anti-IFI16 negative patients (p = 0.018). Within a 6-month follow-up, 14 (33.3%) patients suffered from DPDU, and the prevalence of anti-IFI16 antibodies in patients with DPDU was 42.9%, remarkably higher than 7.1% in those without DPDU (p = 0.012). Additionally, patients with DPDU were more likely to have digital ulcers (DUs) at enrollment and manifest lower finger pulp blood flow, lower ulnar artery (UA) flow velocity, lower UA resistance index, and higher UA resistance index at baseline in comparison to patients without DPDU. Multivariate analysis further identified DUs at enrollment (OR 5.81; 95% CI 1.09-30.86; p = 0.046) and the positivity of anti-IFI16 antibody (OR 8.64; 95% CI 1.05-70.87; p = 0.045) as independent risk factors for DPDU. Presence of anti-IFI16 antibody is associated with higher UA resistance index in SSc. Multivariate analysis further identified anti-IFI16 antibody as a predictive marker for DPDU in SSc. Key Points • SSc patients who were positive for anti-IFI16 antibodies manifested higher ulnar artery resistance at baseline. • The prevalence of anti-IFI16 antibodies in patients with DPDU during the 6-month follow-up was remarkably higher than those without DPDU. • Multivariate analysis identified DUs at enrollment and anti-IFI16 antibody positivity as independent risk factors for DPDU. • Anti-IFI16 antibody is associated with peripheral vasculopathy in SSc. Multivariate analysis further identified anti-IFI16 as a predictive biomarker for the development of DUs.