Crack cocaine has become a major drug of abuse in the United States and its use is associated with a broad spectrum of pulmonary complications. The present study was conducted to determine whether controlled in vivo administration of cocaine (inhaled or IV) alters the function of circulating inflammatory cells in a manner capable of contributing to acute lung injury. Subjects who regularly smoked crack cocaine were asked to abstain from illicit drug use for at least 8 h, and were then administered one of the following treatments on each of 4 study days: inhaled cocaine base (45 mg), inhaled placebo (4.5 mg cocaine base, a subphysiologic dose), IV cocaine HCl (0.35 to 0.50 mg/kg), or IV placebo (saline solution). Samples of blood were obtained from a peripheral venous catheter and blood cells were isolated before and 10 to 45 min after treatment. The administration of either cocaine base or cocaine HCl, but not their corresponding placebos, resulted in the activation of circulating polymorphonuclear neutrophils (PMNs). Exposure to cocaine in vivo enhanced the antibacterial activity of PMNs, as measured by their ability to kill Staphylococcus aureus. Antitumor activity, as measured in an antibody-dependent cell-mediated cytotoxicity assay, also increased following short-term administration of cocaine. Finally, short-term exposure to cocaine enhanced production of interleukin 8, a potent PMN chemoattractant and neutrophil-activating factor associated with both acute and chronic lung injury. These studies demonstrate that short-term in vivo exposure to cocaine activates the effector function and cytokine production of circulating PMNs. Therefore, it is possible that bursts of acute inflammatory activity resulting from crack use could contribute to lung injury.