Abstract Asthma is a heterogeneous airway disease that has increased significantly in recent decades. Clinical studies have shown a positive correlation between serum large high-density lipoprotein (HDL) levels and airway protective effects in asthma. However, how cholesterol communicates with the lung during asthma is still not well understood. Scavenger receptor class B type I (SR-BI) is an HDL receptor that has also been shown to regulate glucocorticoid production. SR-BI has also been shown to regulate lymphocyte apoptosis in models of sepsis and atherosclerosis. Recently, we reported that SR-BI dampens the pulmonary innate immune response, but the role of SR-BI in asthma is unknown. Therefore, SR-BI+/+ and SR-BI−/− mice were sensitized with 10 μg house dust mite (HDM) or PBS by oropharyngeal aspiration on day 0, 7, and challenged with 2 μg HDM on day 14, 15, 16. Airway inflammation, cytokines, and serum corticosterone levels were quantified on day 17. SR-BI−/−mice had increased pulmonary neutrophils and lymphocytes after HDM challenge when compared to SR-BI+/+ mice. SR-BI−/− mice had consistently lower levels of serum corticosterone after HDM or PBS exposure. To determine the role of glucocorticoid production in asthma, SR-BI+/+ and SR-BI−/− mice were supplemented with corticosterone in their drinking water during HDM exposure. SR-BI−/− mice with corticosterone treatment had a decrease in pulmonary lymphocytes after HDM exposure. The observed decrease in lymphocytes may be due to glucocorticoid induced apoptosis which was absent in SR-BI−/− mice not treated with glucocorticoids. Our study has shed new light on how cholesterol receptors such as SR-BI play an important role in glucocorticoid mediated lymphocyte apoptosis in asthma.