Dendritic cells are potent antigen-presenting cells and critical regulators of T-cell responses. We postulated that an important mechanism by which smoking predisposes a person to cancer is by suppressing dendritic cell function, thus inhibiting the ability of dendritic cells to stimulate appropriate T-cell responses. To test this hypothesis, human monocyte-derived dendritic cells were incubated with freshly prepared cigarette smoke extract (CSE) [0 to 2%; mean (± SD) nicotine content in 1% CSE, 2.3 ± 0.8 μg/mL] for the final 18 to 24 h of culture. Dendritic cells were then washed to remove all residual CSE and were incubated with allogenic purified T cells in a mixed lymphocyte reaction for 72 h. T-cell proliferation was measured by the incorporation of tritiated thymidine and cytokine levels into the mixed lymphocyte reaction measured by enzyme-linked immunosorbent assay. The transient incubation of immature dendritic cells with CSE at doses that did not affect viability (as measured by the XTT assay, trypan blue exclusion, and annexin V/propidium iodide staining) resulted in significant suppression of dendritic cell-induced T-cell proliferation. This decrease in T-cell proliferation was accompanied by reduced interferon-γ production, but not in interleukin-4 or interleukin-10 secretion. Dendritic cell surface expression of major histocompatibility complex class II, major histocompatibility complex class I, CD-40, CD-80, CD-86, CD-83, and CD-1a was not altered by transient exposure (ie, for 24 h) to CSE at the same concentrations that diminished dendritic cell-induced T-cell proliferation. These data indicate that transient exposure to CSE causes the selective suppression of dendritic cell functions in the induction of T-cell proliferation and the production of interferon-γ.