Interleukin (IL)-35 is a heterodimeric cytokine composed of the IL-12A subunit and the Epstein-Barr virus induced gene 3 (EBI3) subunit. Binding of IL-35 with IL-12 receptor subunit beta 2 (IL-12RB2) and IL-6 signal transducer (IL-6ST) occupies the binding sites of IL-6, IL-12, and IL-27 and prevents their signal transduction. IL 35 is also shown to promote the development of regulatory T cells (Tregs) and regulatory B cells (Bregs). In this study, we investigated B cell-mediated IL-35 production in patients with coronary artery disease (CAD). The expression levels of IL-35 subunits and IL-10 were significantly lower in B cells from CAD patients than in B cells from healthy control individuals. Exogenous IL-35 could effectively increase the IL-10 production by B cells in a concentration-dependent manner. IL-35 promoted the phosphorylation of STAT1 and STAT3 in B cells, and the inhibition of STAT3 phosphorylation suppressed IL-10 production. Raising the IL-35 concentration in cell culture eliminated the difference in IL-10 expression between CAD B cells and healthy B cells. We also demonstrated that B cells from CAD patients presented lower capacity to suppress interferon gamma (IFNG) and tumor necrosis factor (TNF) expression by T cells than B cells from healthy controls. Exogenous IL-35 could significantly improve the suppressive capacity of B cells in both healthy controls and CAD patients. Together, these results demonstrated that a reduction in IL-35 production was associated with Breg defects in CAD patients. IL-35 and IL-35 targets may serve as therapeutic candidates in the treatment of CAD and related diseases.