Apoptosis, or 'programmed cell death' is a process of general biological relevance with implications in several physiological and pathological conditions of the skin. However, little is known about its induction in keratinocytes by regulator agents. In this work we demonstrate that IFNbeta, but not IFNalpha, selectively induces programmed cell death in HPK-Ia cells, a line derived from human keratinocytes transformed with HPV-16 DNA. This IFNbeta-triggered apoptosis is strictly dependent on a serum-induced partially differentiated phenotype; it occurs through the activation of a check point in the early 'S' phase, where the cells are arrested and eventually driven to apoptosis. These data indicate that apoptosis may be induced in keratinocytes by a regulator agent combined with a differentiating stimulus.