Administration of cyclosporin A (CsA; 25 mg/kg) orally to guinea pigs from the time of immunization with ovalbumin (OVA) in complete Freund's adjuvant, followed by drug withdrawal 4 days later, resulted in marked potentiation of classical, tuberculin-like delayed-hypersensitivity skin responses to OVA. However, no such augmentation of delayed-type hypersensitivity (DTH) to purified protein derivative (PPD) was demonstrated. The enhancing effect of CsA was also dependent on the dose of OVA used for both immunization and skin testing and on the interval between drug withdrawal and the elicitation of DTH. A single intraperitoneal injection of CsA (200 mg/kg) given 2 days before immunization also had an augmentary effect on 14-day responses to OVA. Similar treatment protocols, however, did not enhance Jones-Mote (cutaneous basophil) hypersensitivity to OVA or contact sensitivity reactions to dinitrofluorobenzene. Longer courses of CsA (25 mg/kg per os) between sensitization and skin testing severely depressed all three categories of type IV hypersensitivity reactions. Our observations may have important cautionary implications for the prospective management of immunologically mediated diseases of intermittent activity, including certain autoimmune disorders, where short courses of CsA might be contemplated.