Objective To induce skin cancer in BALB/c mice using DMBA as initiator and TPA as tumor promoter. Through optimizing the doses and frequencies of DMBA administration to establish a stable skin cancer model with less time and causing less skin damage. Methods Shaving the back of mice to expose a piece of skin around 2 cm×2 cm. The mice were divided into a blank control group and four treatment groups randomly. These four groups were given 1, 2, 4, 7 times 100 μg/100 μL DMBA/acetone, respectively, in the first week, and twice 4 μg/100 μL TPA/acetone per week in the next 11 weeks. The body weight changes, time of tumor formation and number of tumors formed were recorded during the experiment. The mice were sacrificed at 12th week and samples of tumor tissue and adjacent normal skin tissue were taken for pathological examination using HE staining. Results Tumors were observed at the 7th week in the group with once DMBA administration in the first week and at the 4th week in the group with twice DMBA administration in the first week. Skin cancers were formed also in the group with 4-time DMBA administration in the first week, however, with significantly more severe skin damages. The mice receiving DMBA everyday in the first week died at the 3th week. Conclusions The best induction protocol for skin cancer in BALB/c mice should be twice DMBA in the first week followed by twice TPA in the next few weeks. This protocol has the advantages of easy operation, short modeling time, high cancer formation rate, and presents a similar process of human skin carcinogenesis, thus, it can be used as a useful animal model for skin cancer research.