Previous reports demonstrated that long-term exposure to extremes in humidity influence permeability barrier homeostasis. Here the effects of a sudden shift from a high humidity to a dry environment were studied. Mice were initially maintained in either a humid (> 80% relative humidity) or normal environment (relative humidity = 40-70%), and then transferred to a dry environment (< 10% relative humidity). Within 2 d of transfer from a humid to a dry environment a 6-7-fold increase in transepidermal water loss occurred that returned to normal within 7 d. No increase in transepidermal water loss occurred in response to a switch from a normal to a dry environment. At a time when barrier function was abnormal, both stratum corneum hydration and pH were normal, indicating that the mechanisms that regulate these functions differ. Following transfer from a humid to dry environment, electron microscopy revealed a marked decrease in: (i) lamellar bodies in the outermost stratum granulosum; (ii) deposition of lamellar body contents at the stratum granulosum-stratum corneum interface; and (iii) the quantity of intercellular lamellae in the stratum corneum, which together could account for the barrier abnormality. Transfer of mice from a normal to a dry environment rapidly stimulated epidermal proliferation, whereas animals switched from a humid to a dry environment displayed a delayed increase in proliferation that might also contribute to the barrier abnormality. The present study demonstrates that sudden changes from a high to a low humidity environment results in abnormal barrier function, which could adversely influence the incidence and/or severity of skin disorders.