Delayed-type skin allergic (DTA) reactions induced by various sulfhydryl compounds were investigated. Sulfhydryl compounds investigated were bucillamine and D-penicillamine: antirheumatic agents, SA981: an intramolecular cyclic disulfide of bucillamine, tiopronin: a hepatoprotective and potent antirheumatic agent and captopril: antihypertensive and potent antirheumatic agent. Guinea pigs were sensitized on day 1 by subcutaneous injection and day 7 by subcutaneous and intramuscular injection of emulsions of these compounds (3 mg/animal) with Freund's complete adjuvant. Two weeks after the second sensitization, 0.3 mg/animal of each compound was intradermally challenged and the 24 hr DTA reaction was evaluated. A large number of sulfhydril compounds showed positive in the DTA reactions and the intensity of these reactions had a good correlation with the frequency of the skin rashes referred to by the adverse effects in clinical reports of anti-rheumatic drugs. It is suggested that guinea pig DTA reaction may provide a good screening way to find new sulfhydryl or disulfide compounds with low incidence of skin rash. A novel sulfhydryl compound N-(2,2-dimethyl-3-mercaptopropionyl)-L-cysteine (SA3441) and its intramolecular cyclic disulfide (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (SA3443), which show no DTA activity in guinea pigs, were found using the above-mentioned DTA reaction.