Previous studies have shown that pH declines from between 6 and 7 at birth to adult levels (pH 5.0-5.5) over 5-6 days in neonatal rat stratum corneum (SC). As a result, at birth, neonatal epidermis displays decreased permeability barrier homeostasis and SC integrity, improving days 5-6. We determined here whether peroxisome proliferator-activated receptor (PPAR) activators accelerate postnatal SC acidification. Topical treatment with two different PPARalpha activators, clofibrate and WY14643, accelerated the postnatal decline in SC surface pH, whereas treatment with PPARgamma activators did not and a PPARbeta/delta activator had only a modest effect. Treatment with clofibrate significantly accelerated normalization of barrier function. The morphological basis for the improvement in barrier function in PPARalpha-treated animals includes accelerated secretion of lamellar bodies and enhanced, postsecretory processing of secreted lamellar body contents into mature lamellar membranes. Activity of beta-glucocerebrosidase increased after PPARalpha-activator treatment. PPARalpha activator also improved SC integrity, which correlated with an increase in corneodesmosome density and increased desmoglein-1 content, with a decline in serine protease activity. Topical treatment of newborn animals with a PPARalpha activator increased secretory phospholipase A2 activity, which likely accounts for accelerated SC acidification. Thus, PPARalpha activators accelerate neonatal SC acidification, in parallel with improved permeability homeostasis and SC integrity/cohesion. Hence, PPARalpha activators might be useful to prevent or treat certain common neonatal dermatoses.