Rationale: Despite ongoing research, the molecular mechanisms controlling asthma are still elusive. CD48 is a glycosyl-phosphatidyl-inositol anchored protein involved in lymphocyte adhesion, activation and co-stimulation. While CD48 is widely expressed on hematopoietic cells and commonly studied in the context of NK and cytotoxic T cell functions, its role in Th2-settings has not been examined. Objective: To evaluate the expression and function of CD48, CD2 and 2B4 in a murine model of allergic-eosinophilic airway inflammation. Methods: Allergic-eosinophilic airway inflammation was induced by OVA/Alum sensitization and intranasal inoculation of OVA or alternatively by repeated intranasal inoculation of Aspergillus fumigatus antigen in wild type, STAT-6-deficient, and IL-4/IL-13-deficient BALB/c mice. Gene profiling of whole-lung was performed, followed by northern blot and flow cytometric analysis. Anti-CD48, -CD2 and -2B4 antibodies were administered before OVA challenge and cytokine expression and histology were assessed. Main Results: Microarray data analysis demonstrated upregulation of CD48 in the lungs of OVA-challenged mice. Allergen-induced CD48 expression was STAT-6-, IL-13- and IL-4-independent. Neutralization of CD48 in allergen-challenged mice abrogated BALF and lung inflammation. Neutralization of CD2 inhibited the inflammatory response to a lesser extent and neutralization of 2B4 had no effect. Conclusions: Our results suggest that CD48 is critically involved in allergic eosinophilic airway inflammation. As such, CD48 may provide a new potential target for the suppression of asthma.