Annona muricata L (Annonaceae), commonly known as soursop has a long, rich history in herbal medicinewith a lengthy recorded indigenous use. It had also been found to be a promising new anti-tumor agent innumerous in vitro studies. The present investigation concerns chemopreventive effects in a two-stage modelof skin papillomagenesis. Chemopreventive effects of an ethanolic extract of A. muricata leaves (AMLE) wasevaluated in 6-7 week old ICR mice given a single topical application of 7,12-dimethylbenza(α)anthracene (DMBA100ug/100ul acetone) and promotion by repeated application of croton oil (1% in acetone/ twice a week) for 10weeks. Morphological tumor incidence, burden and volume were measured, with histological evaluation of skintissue. Topical application of AMLE at 30, 100 and 300mg/kg significantly reduced DMBA/croton oil inducedmice skin papillomagenesis in (i) peri-initiation protocol (AMLE from 7 days prior to 7 days after DMBA), (ii)promotion protocol (AMLE 30 minutes after croton oil), or (iii) both peri-initiation and promotion protocol(AMLE 7 days prior to 7 day after DMBA and AMLE 30 minutes after croton oil throughout the experimentalperiod), in a dose dependent manner (p<0.05) as compared to carcinogen–treated control. Furthermore, theaverage latent period was significantly increased in theAMLE-treated group. Interestingly, At 100 and 300 mg/kg, AMLE completely inhibited the tumor development in all stages. Histopathological study revealed that tumorgrowth from the AMLE-treated groups showed only slight hyperplasia and absence of keratin pearls and reteridges. The results, thus suggest that the A.muricata leaves extract was able to suppress tumor initiation as wellas tumor promotion even at lower dosage.