Interstitial lung disease, although of prognostic impact for patients with cystic fibrosis (CF), remains difficult to assess without histopathologic investigations. As changes of peripheral blood lymphocyte subsets (LS) may accompany severe systemic lymphocyte immune responses, we compared peripheral LS of 44 patients with CF, 23 non-CF patients with recurrent pulmonary infections and 83 healthy controls (flow cytometry; CD3, CD19, CD16, CD56, CD4, CD8, CD11b, CD45RA, CD45RO, HLA-DR and CD25 antigens). Additional immunohistochemistry was performed on lung tissue of four CF patients aged 0.5, 12, 17 and 20 years, respectively. Patients with CF showed low absolute counts of CD4+CD45RO+ memory helperT cells, CD16+CD56+ NK cells, CD8+ and interleukin-2 receptor-positive T cells in peripheral blood (P < 0.001). Similar changes were registered in the non-CF patients with pulmonary infections, indicating that those were not specific for CF. Immunohistochemistry showed activation of bronchus-associated lymphoid tissue with interstitial accumulation of CD4+CD45 RO+ T cells in the three older patients. Patients with CF show marked changes of peripheral blood LS which are presumably not CF-specific and may mirror homing to lung tissue in the course of interstitial lung disease. Further research should evaluate its usefulness in monitoring progression of lung disease in CF.