Vascular endothelial growth factor (VEGF) is an important mitogen with multiple functions. In the present study we investigated whether T cell secreted VEGF and inflammatory cytokines were modulated by cigarette smoke and by a hypoxic microenvironment. T cells from peripheral blood of healthy donors were activated under normoxia (21% O(2)) or hypoxia (1-2% O(2)) with or without exposure to cigarette smoke extract. T cells were also obtained from patients with chronic obstructive pulmonary disease (COPD), a smoking-related disease characterized by accumulation of both CD4+ and CD8+T cells. Hypoxia stimulated VEGF secretion from activated T cells, whereas the release of IL-4, IL-6, IL-10, IL-13, IFN-gamma and tumour necrosis factor were not altered. Cigarette smoke extract did not affect VEGF secretion neither in hypoxia nor in normoxia, whereas the secretion of all cytokines was inhibited by the extract in both conditions. When recombinant VEGF was added the smoke-induced inhibition of the IFN-gamma and IL-13 was not observed. Activated T cells from COPD-patients secreted significantly (p < 0.05) more VEGF compared to T cells from healthy individuals. Our data suggest that both cigarette smoke extract and hypoxia modulate the T cell response. This may be of importance in diseases characterized by T cell accumulation, such as COPD.