AbstractGlycolic acid, an alpha‐hydroxy acid derived from fruit and milk sugars, has been used commonly as a cosmetic ingredient since it was discovered to have photoprotective and anti‐inflammatory effects and antioxidant effects on ultraviolet (UV)B–irradiated skin. Little is known, however, about the functional role of glycolic acid on UV‐induced skin tumorigenesis. In the present study, we examined the effect of glycolic acid on UV (UVA + UVB)–induced skin tumorigenesis and assessed several significant contributing factors in SKH‐1 hairless mice. Inbred hairless female mice (15 animals/group) were irradiated for 5 d/wk at a total dose of 74.85 J/cm2 UVA and 2.44 J/cm2 UVB for 22 wk. Glycolic acid was applied topically twice a week at a dose of 8 mg/cm2 immediately after UV irradiation. Glycolic acid reduced UV‐induced skin tumor development. The protective effect of glycolic acid was a 20% reduction of skin tumor incidence, a 55% reduction of tumor multiplicity (average number of tumors/mouse), and a 47% decrease in the number of large tumors (larger than 2 mm). Glycolic acid also delayed the first appearance of tumor formation by about 3 wk. The inhibitory effect of glycolic acid on UV‐induced tumor development was accompanied by decreased expression of the following UV‐induced cell‐cycle regulatory proteins: proliferating cell nuclear antigen (PCNA), cyclin D1, cyclin E, and the associated subunits cyclin‐dependent kinase 2 (cdk2) and cdk4. In addition, the expression of p38 kinase, jun N‐terminal kinase (JNK), and mitogen‐activated protein kinase kinase (MEK) also was lower in UV + glycolic acid–treated skin compared with expression in UV‐irradiated skin. Moreover, transcription factors activator protein 1 (AP‐1) and nuclear factor κB (NF‐κB) activation was significantly lower in UV + glycolic acid–treated skin compared with activation in UV‐irradiated skin. These results show that glycolic acid reduced UV‐induced skin tumor development. The decreased expression of the cell‐cycle regulatory proteins PCNA, cyclin D1, cyclin E, cdk2, and cdk4 and the signal mediators JNK, p38 kinase, and MEK may play a significant role in the inhibitory effect of glycolic acid on UV‐induced skin tumor development. In addition, the inhibition of activation of transcription factors AP‐1 and NF‐κB could contribute significantly to the inhibitory effect of glycolic acid. © 2001 Wiley‐Liss, Inc.