Pulmonary hypertension (PH) is a severe cardiopulmonary disease characterized by pulmonary vascular remodeling. Immunoglobulin E (IgE) is known to participate in aortic vascular remodeling, but whether IgE mediates pulmonary vascular disease is unknown. In the present study, we found serum IgE elevation in pulmonary arterial hypertension (PAH) patients, hypoxia-induced PH mice and monocrotaline-induced PH rats. Neutralizing IgE with an anti-IgE antibody was effective in preventing PH development in mice and rat models. The IgE receptor FcεRIα was also upregulated in PH lung tissues and Fcer1a deficiency prevented the development of PH. Single-cell RNA-sequencing revealed that FcεRIα was mostly expressed in mast cells (MCs) and MC-specific Fcer1a knockout protected against PH in mice. IgE-activated MCs produced interleukin (IL)-6 and IL-13, which subsequently promoted vascular muscularization. Clinically approved IgE antibody omalizumab alleviated the progression of established PH in rats. Using genetic and pharmacological approaches, we have demonstrated that blocking IgE-FcεRIα signaling may hold potential for PAH treatment.