Objective Semaphorin 3A (Sema3A) plays a regulatory role in immune responses. The aim of this study was to evaluate Sema3A levels in patients with systemic sclerosis (SSc), especially in major vascular involvements such as digital ulcer (DU), scleroderma renal crisis (SRC), pulmonary arterial hypertension (PAH), and to compare Sema3A level with SSc disease activity. Methods In SSc patients, patients with DU, SRC, or PAH were grouped as major vascular involvements and those without as nonvascular, and Sema3A levels were compared between the groups and with a healthy control group. The Sema3A levels and acute phase reactants in SSc patients, as well as their association with the Valentini disease activity index and modified Rodnan skin score, were evaluated. Results The Sema3A values (mean ± SD) were 57.60 ± 19.81 ng/mL in the control group (n = 31), 44.32 ± 5.87 ng/mL in patients with major vascular involvement SSc (n = 21), and 49.96 ± 14.00 ng/mL in the nonvascular SSc group (n = 35). When all SSc patients were examined as a single group, the mean Sema3A value was significantly lower than controls (P = .016). The SSc with major vascular involvement group had significantly lower Sema3A levels than SSc with nonmajor vascular involvement group (P = .04). No correlation was found between Sema3A, acute phase reactants, and disease activity scores. Also, no relationship was observed between Sema3A levels and diffuse (48.36 ± 11.47 ng/mL) or limited (47.43 ± 12.38 ng/mL) SSc types (P = .775). Conclusion Our study suggests that Sema3A may play a significant role in the pathogenesis of vasculopathy and can be used as a biomarker in SSc patients with vascular complications such as DU and PAH.