3-Hydroxy-sulfanilamide (3-HS), a biotransformation product of sulfanilamide, 3-hydroxy-para-aminobenzoic acid (3- HPABA ), a biotransformation product of procaine and para-aminobenzoic acid, as well as 5-aminosalicylic acid (5-ASA), a bacterial split product of salicylazosulfapyridine (Sulfasalazine, Salazopyrin ) in the gut, were shown to react spontaneously with and to bind covalently to proteins by simple incubation at alkaline pH. When administered incorporated in incomplete Freund adjuvant into rabbits, the conjugates of these haptens with normal rabbit serum proteins (NRS) give rise to both hapten specific and anti-NRS antibodies. The haptenic properties of these drug metabolites are apparently due to the presence in their molecules of an ortho- or para- aminophenolic structure that renders them capable to generate spontaneously highly reactive quinoneimines . Extensive cross immunological reactions were found between 3-HS, 3- HPABA and ortho-aminophenol (OAP) immunological systems, all of these haptens belonging to the ortho- aminophenolic (ortho- quinoneiminic ) system. Cross reactions were also found between 5-ASA and para-aminophenol (PAP) immunological systems, both of these haptens belonging to the para- aminophenolic (para- quinoneiminic ) system. No cross reactions were, however, found between ortho- and para-aminophenol immunological systems. The so-called "para" group of aminoaromatic compounds is not therefore immunochemically homogeneous. Some compounds included usually in this group give rise in the body to haptens belonging to the ortho- aminophenolic systems, while others belong really to the para- aminophenolic system. Antibodies against NRS proteins which served as carrier in the conjugates were formed by most animals inoculated with such conjugates. (ABSTRACT TRUNCATED AT 250 WORDS)