After the epidermal permeability barrier is mechanically abrogated by sequential tape stripping, transepidermal water loss (TEWL) across the stratum corneum (SC) returns to baseline in parallel with accelerated synthesis of cholesterol, ceramides and free fatty acids. Aged hairless mice (> 18 months) exhibit a delay in barrier recovery in conjunction with decreased rates of lipid synthesis and deposition in the SC (Ghadially, et al., J. Clin. Invest. 95:2281-2290, 1995). Prior studies in young mice (<10 weeks) have shown that application of a lipid mixture of cholesterol, ceramides, palmitic acid and linoleic acid in an equimolar ratio allows for normal barrier recovery, whereas a ratio of 3:1:1:1 accelerates barrier recovery by approximately 35% at 4 and 6 hours after barrier injury (Mao-Qiang, et al., Arch. Dermatol. 131:809-816, 1995; Yang, et al., Br. J. Dermatol. 133:679-685, 1995).We investigated the effect of the equimolar lipid mixture and the optimal molar mixture (2% in propylene glycol:ethanol, 7:3) vs. vehicle alone on barrier recovery in aged (>21 months) hairless mice. Barrier recovery was assessed at 0,3,6,24 and 48 hours after tape stripping, using a Mecco electrolytic water analyzer to measure transepidermal water loss. Controls included both vehicle alone and an untreated site. Whereas the equimolar mixture improved barrier recovery by approximately 11±2% at 6 hours, the optimal mixture improved barrier recovery by approximately 25±5% at 3 hours and 25±2% at 6 hours after barrier abrogation. These findings underscore the dramatic acceleration of epidermal barrier repair that can be obtained with optimal lipid ratios, and show that topical physiological lipids improve the compromised epidermal barrier in aged epedermis.