A reaction of the basic amino acids, lysine and arginine, with components of cigarette smoke has been observed. The adducts produced have been identified as cyanomethyl derivatives. Both formaldehyde and cyanide, which are known to be present in cigarette smoke, are involved in the reaction with the primary amino group. The reaction is time-dependent and can be enhanced by an increase of temperature or by incubation under alkaline conditions. Cyanomethyl adduct formation was found to be increased when smoke from cigarettes with higher tar and nicotine content was used. When proteins, such as bovine serum albumin, trypsin inhibitors or crude rat lung proteins were incubated with the cigarette smoke solution, new protein adducts with increased pI values were produced which are separable from the original proteins by gel isoelectric focussing. Radioisotopically labelled cyanide can be irreversibly linked to protein and the linkage is enhanced in the presence of formaldehyde.