BACKGROUND AND DESIGN: The efficacy of topical tretinoin (all-trans-retinoic 
acid) in treating photoaging is well established. Questions that remain are (1) 
whether irritation causes all or part of the improvement; (2) the concentration 
of tretinoin that maximizes clinical response with minimal side effects; and (3) 
the effects of long-term treatment on components of the cutaneous immune system. 
To address these issues, 99 photoaged patients completed a 48-week study using 
0.1% tretinoin cream (n = 32), 0.025% tretinoin (n = 35), or vehicle (n = 32) 
once daily in a double-blind manner. Before and after treatment, we assessed 
histologic features, keratinocyte expression of HLA-DR and intercellular 
adhesion molecule-1, numbers of epidermal Langerhans' cells and epidermal and 
dermal T lymphocytes, and vascularity as measured by dermal endothelial cell 
area.
RESULTS: Both 0.1% and 0.025% tretinoin produced statistically significant 
overall improvement in photoaging of the face compared with vehicle; there were 
no clinically or statistically significant differences in efficacy between the 
two concentrations of tretinoin. After 48 weeks, 0.1% and 0.025% tretinoin 
produced similar statistically significant epidermal thickening (by 30% and 28%, 
respectively) compared with vehicle (11% decrease) and increased vascularity (by 
100% and 89%, respectively) compared with vehicle (9% decrease). By various 
analyses, irritant side effects (erythema and scaling) were statistically 
significantly greater with 0.1% tretinoin than with 0.025% tretinoin. No 
significant changes occurred in any immunologic markers when tretinoin and 
vehicle treatments were compared.
CONCLUSIONS: Tretinoin 0.1% and 0.025% produce similar clinical and histologic 
changes in patients with photoaging, despite significantly greater incidence of 
irritation with the higher concentration. The separation between clinical 
improvement and irritation suggests that mechanisms other than irritation 
dominate tretinoin-induced repair of photoaging in humans.