Normal and sickle erythrocytes were exposed in vitro to millimolar concentrations of 31 different carbonyl compounds. Schiff base (imine) linkages were formed with amino groups of intracellular hemoglobin. Adducts were isolated by gel electrofocusing and could be dissociated by dialysis. Aromatic aldehydes proved more reactive than aliphatic aldehydes, and ketones were unreactive. The influence of various ring substituents on the reactivity of aromatic aldehydes was found to conform closely to traditional concepts regarding electronic and steric effects. Several of the aromatic aldehydes were shown to markedly increase the oxygen affinity of hemoglobins A and S. In particular, 2,4-dihydroxybenzaldehyde and o-vanillin, at concentrations of 5 mM, produced 2- to 3-fold reductions in the P50 (partial pressure of oxygen at half-saturation) of sickle hemoglobin in whole blood. Since low degrees of oxygen saturation promote erythrocyte sickling, compounds of this type significantly inhibit sickling at reduced partial pressures of oxygen.