The principal objective of this research has been to determine the safety of inhaled glucocorticoids (GCs) in respect of their effect on CD8+ T cells within respiratory and extra-respiratory tissues, and to compare it with systemic GC treatment. Another purpose has been to identify whether inhaled and systemic GCs affect the CD8+ T cell response in the mediastinal lymph nodes (MLNs) and lungs in a mouse model of ovalbumin (OVA)-induced asthma. Ciclesonide and methylprednisolone were used as a model for inhaled and systemic GCs, respectively. The CD8+ T cell response was observed in untreated OVA-immunized mice, manifesting itself by the proliferation of these cells and their recruitment into the lower respiratory tract. Inhaled and systemic GC treatment fully prevented this response. This suggests that one of the elements contributing to the anti-asthmatic efficacy of inhaled and systemic GCs could be the inhibition of the effector CD8+ T cell response which accompanies the disease. The anti-asthmatic effect of GCs was rather not mediated through the generation or/and increased recruitment of Foxp3+CD25+CD8+ regulatory T cells into the MLNs and lungs. Inhaled and systemic GCs produced comparable depletions of normal CD8+ T cells in the MLNs, the head and neck lymph nodes and in peripheral blood, and this effect, at least to some extent, resulted from the proapoptotic action of GCs towards these cells. These results suggest that inhaled GC therapy might not be safer at all than treatment with systemic GCs in respect of the undesirable effects on CD8+ T cells residing within and outside the respiratory tract.