Over the past 20 years, protein glycation has been implicated in a variety of pathological states. Although smoking also can contribute to many of these diseases, the precise mechanism by which this occurs is not known. Previously, we have demonstrated that nornicotine, a constituent of tobacco and metabolite of nicotine, can catalyze aldol reactions under aqueous conditions. This finding has caused us to question whether this reaction has physiological consequences. We now report that nornicotine causes aberrant protein glycation and catalyzes the covalent modification of certain prescription drugs such as the commonly used steroid, prednisone. Furthermore, we show that the plasma of smokers as compared with nonsmokers contains higher concentrations of nornicotine-modified proteins, suggesting an unrecognized pathway for the development of the pathology of tobacco abuse.