Pretreatment by topical application of 8-methoxypsoralen and subsequent exposure to long-wave ultraviolet light (PUVA) on the induction site of contact sensitization to dinitrochlorobenzene (DNCB) significantly diminished the challenge reactions in guinea pigs. A single treatment with PUVA in a small area was enough to exhibit such an effect. Furthermore, the animals that had been first exposed to DNCB through PUVA-treated skin failed to become sensitized to the subsequent sensitization regimen of the same hapten even through previously untreated skin. The unresponsiveness in these animals was hapten-specific, since their capacity to become sensitized to an unrelated hapten, oxasolon, was not impaired. The intraperitoneal administration of cyclophosphamide at a dose of 200 mg/kg shortly before contact sensitization reversed the unresponsiveness in tolerant animals. These findings suggest that tolerance in these animals is a specific immunologic unresponsiveness mediated by suppressor cells.