Brief exposure to cigarette smoke is not generally associated with pulmonary injury and may adversely affect the lung only if underlying disease is present. To test this hypothesis, our laboratory performed a series of experiments involving exposure of hamsters to second-hand cigarette smoke (2 h/day for 5 days), either immediately before or after induction of acute pulmonary injury by intratracheal administration of amiodarone. Compared to controls receiving amiodarone alone, hamsters pretreated with smoke showed significant increases in the following parameters: (1) lung inflammation graded on a scale of 0-4 (3.4 vs. 1.6; p < 0.001), (2) percentage of neutrophils in bronchoalveolar lavage fluid (BALF) (75.0 vs. 1.3; p < 0.001), (3) percentage of TNFR1-positive BALF macrophages (44.7 vs. 2.7; p < 0.001), and (4) apoptotic lung parenchymal cells per ten high-power microscopic fields (7.3 vs. 0.7; p < 0.001). Animals post-treated with smoke also showed significant increases in these parameters compared to controls but to a lesser degree than pre-exposed animals. With regard to human disease, such synergistic interactions may account for a significant portion of the morbidity associated with second-hand smoke exposure.