Objective-Interleukin-12 is essential for the differentiation of naive T cells into interferon-gamma-producing T cells, which regulate inflammatory responses. We investigated this process of regulating hypertension-induced cardiac fibrosis. Methods and Results-Mice infused with angiotensin II showed a marked increase in interleukin-12p35 expression in cardiac macrophages. The degree of cardiac fibrosis was significantly enhanced in interleukin-12p35 knockout (p35-KO) mice compared with wild-type (WT) littermates in response to angiotensin II. Fibrotic hearts of p35-KO mice showed increased accumulation of alternatively activated (M2) macrophages and expression of M2 genes such as Arg-1 and Fizz1. Bone marrow-derived macrophages from WT or p35-KO mice did not differ in differentiation in response to angiotensin II treatment; however, in the presence of CD4(+) T cells, macrophages from p35-KO mice differentiated into M2 macrophages and showed elevated expression of transforming growth factor-beta. Moreover, CD4(+) T-cell-treated p35-KO macrophages could stimulate cardiac fibroblasts to differentiate into alpha-smooth muscle actin-positive and collagen I-positive myofibroblasts in 3-dimensional nanofiber gels. Neutralizing antibodies against transforming growth factor-beta inhibited myofibroblast formation induced by M2 macrophages. Conclusion-Deficiency in interleukin-12p35 regulates angiotensin II-induced cardiac fibrosis by promoting CD4(+) T-cell-dependent differentiation of M2 macrophages and production of transforming growth factor-beta. (Arterioscler Thromb Vasc Biol 2012;32:1662-1674.)