Abstract The primary ocular and dermal irritations of four quaternary ammonium compounds, namely cetylpyridinium chloride (CPC), stearylphenylethyldimethylammonium tosylate (SPDAT), dimethyldis-tearylammonium bisulfate (DDABS) and tri(n-butyl)benzylammonium 4-hydroxynaphthalene-l-sulfonate (TBAHNS), were studied. Both CPC and SPDAT were extremely or severely irritating to the eyes of the test animals, whereas DDABS and TBAHNS were mildly or minimally irritating. Both CPC and SPDAT were also severely or extremely irritating to the skin of the test animals, while DDABS and TBAHNS were non-irritating. These quaternary ammonium compounds have little similarity in chemical structure and possess different solubilities. CPC is very soluble in both lipid and water; SPDAT is very soluble in lipid but only slightly soluble in water; and DDABS and TBAHNS are poorly soluble in either lipid or water. The irritancy of these compounds is likely to be related to their solubility, in addition to the cationic characteristics. It appears that not all quaternary ammonium compounds in this study are irritants. Those that are not soluble are not expected to be absorbed in eye/skin tissues and thus irritation reactions will not take place. The use of in vitro alternatives should be considered when assessing the ocular and dermal irritancy potential of water- and lipid-soluble quaternay ammonium compounds.