Objective: To investigate the expression levels and clinical significance of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in peripheral blood mononuclear cells (PBMCs) and plasma of patients with systemic sclerosis (SSc). Methods: Peripheral blood samples were collected from 32 SSc patients (SSc group) and 32 healthy controls (HC group). PBMCs and plasma were isolated and extracted. The mRNA and protein expression levels of BAFF and APRIL in PBMCs were detected using real-time quantitative PCR (RT-qPCR) and Western blot, respectively. Plasma concentrations of the corresponding proteins were measured by ELISA. Correlations with clinical indicators were analyzed, and the diagnostic value for SSc was evaluated using receiver operating characteristic (ROC) curves. Results: Both mRNA and protein expression levels of BAFF and APRIL in PBMCs of SSc patients were higher than those in the HC group (P<0.05). Plasma BAFF levels were positively correlated with erythrocyte sedimentation rate (r=0.60), high-sensitivity C-reactive protein (r=0.40), anti-Scl-70 antibody (r=0.57), and joint involvement (r=0.39) (P<0.05), and negatively correlated with estimated glomerular filtration rate (r=-0.37) (P<0.05). APRIL levels were positively correlated with interstitial lung disease (r=0.52) and high-density lipoprotein (r=0.45) (P<0.05). The areas under the ROC curve (AUC) for diagnosing SSc using BAFF, APRIL, and their combination were 0.759, 0.654, and 0.792, respectively. Conclusion: The expression of BAFF and APRIL is elevated in SSc patients and closely associated with specific autoantibodies, inflammatory status, and organ damage. Combined detection of both markers may improve the diagnostic efficacy for SSc, suggesting their potential as biomarkers and therapeutic targets for SSc.