Activated polymorphonuclear neutrophils (PMNs) may contribute to the genesis of chronic obstructive lung disease in long-term cigarette smokers. However, it is not presently known which elements in smoke are important in triggering this progressive pulmonary damage or in affecting the activities of inflammatory cells such as PMNS. We earlier found substances in organic concentrates of cigarette smoke that bound ferrous iron and transferred the metal into organic phases. These substances were later identified as saturated free fatty acids, predominantly palmitic and stearic acids (16:0 and 18:0). We now report investigations of the effects of fatty acids on the oxidative metabolism of PMNs. In accord with most earlier reports, we find that saturated fatty acids have little direct effect on PMN oxidative metabolism. However, micromolar amounts of free fatty acids will more than double production of hypochlorous acid (HOCl) by PMNs stimulated with small amounts of phorbol myristate acetate. Similar fatty acid-mediated increases in HOCl production also occur when PMNs are stimulated with 1,2-dioctanoyl-sn-glycerol and 1-oleoyl-2-acetyl-sn-glycerol (also thought to be agonists of protein kinase C) but not when cells are stimulated with the calcium ionophore A23187, the formylated tripeptide f-met-leu-phe, or opsonized zymosan. Fatty acid-mediated enhancement of PMN HOCl production evidently arises from increased release of myeloperoxidase from stimulated PMNs. Furthermore, in the presence of free fatty acids, stimulated PMNs are much more cytotoxic toward cultured mink lung epithelial cells, a toxicity that is blocked by scavengers of HOCl. These results suggest that the relatively large amounts of free fatty acids present in tobacco smoke may act to amplify PMN-mediated oxidative damage to the lungs of smokers.