Certain derivatives of diphenyl disulphide are known to cause haemolytic anaemia in rats, by a mechanism possibly involving intra-erythrocytic redox cycling with concomitant generation of ‘active oxygen’ species. In ring-substituted diphenyl disulphide derivatives, electronic effects of substituents have been shown markedly to affect the rate of ‘active oxygen’ production in vitro and toxicity in vivo. In the present study, the influence of steric effects of substituents on these parameters has been investigated. The severity of the haemolysis induced in groups of seven rats by oral dosing with 4,4′-dimethoxydiphenyl disulphide and 4,4′-dimethyldiphenyl disulphide at doses of 500 μmol/kg/day for 6 days was greater than that of the 2,2′ isomers and the haemolytic activity of a series of 2,2′-dialkyl derivatives decreased with increasing size of the alkyl group. In vitro, the haematin-catalysed oxidation rates and the rates of redox cycling of the corresponding thiols in the presence of glutathione were similarly influenced by steric hindrance. The structure-activity relationships identified in the present investigation, together with knowledge of the electronic effects of substituents, should permit accurate prediction of the toxicity of new or untested aromatic thiols and disulphides.