Cysteinyl leukotrienes (cysLTs), leukotriene C₄ (LTC₄), LTD₄, and LTE₄ are proinflammatory lipid mediators with pathobiologic function in asthma. LTE₄, the stable cysLT, is a weak agonist for the type 1 and type 2 cysLT receptors (CysLTRs), which constrict airway smooth muscle, but elicits airflow obstruction and pulmonary inflammation in patients with asthma. We recently identified GPR99 as a high-affinity receptor for LTE₄ that mediates cutaneous vascular permeability. Here we demonstrate that a single intranasal exposure to extract from the respiratory pathogen Alternaria alternata elicits profound epithelial cell (EpC) mucin release and submucosal swelling in the nasal mucosa of mice that depends on cysLTs, as it is absent in mice deficient in the terminal enzyme for cysLT biosynthesis, LTC₄ synthase (LTC₄S). These mucosal changes are associated with mast cell (MC) activation and absent in MC-deficient mice, suggesting a role for MCs in control of EpC function. Of the three CysLTRs, only GPR99-deficient mice are fully protected from EpC mucin release and swelling elicited by Alternaria or by intranasal LTE₄. GPR99 expression is detected on lung and nasal EpCs, which release mucin to doses of LTE₄ one log lower than that required to elicit submucosal swelling. Finally, mice deficient in MCs, LTC₄S, or GPR99 have reduced baseline numbers of goblet cells, indicating an additional function in regulating EpC homeostasis. These results demonstrate a novel role for GPR99 among CysLTRs in control of respiratory EpC function and suggest that inhibition of LTE₄ and of GPR99 may have therapeutic benefits in asthma.