Background: Piper sarmentosum Roxb. is a traditional medicine which can also be consumed as a vegetable. Despite the availability of a variety of toxicological data on extracts of this plant, to our knowledge, until now, no dermal toxicological tests have been conducted. The aim of the present study was, therefore, to carry out in vivo assays to verify the safety of application of P. sarmentosum extract gel on the skin. Materials and Methods: The essential oils were extracted from the dried leaves of P. sarmentosum by hydrodistillation and then formulated into a gel. An in vivo skin irritation test of the P. sarmentosum extract gel was then conducted on albino rabbits, and an in vivo sensitization test was carried out on albino guinea pigs. Results: For both abraded and non-abraded sites, the calculated primary irritation index value for P. sarmentosum was 2.55, indicating that topical use of a gel with P. sarmentosum (1.55%) is nonirritative. However, a dermal sensitization assay revealed mild sensitization effects in 1 out of 10 guinea pigs in response to the application. Histological analysis revealed a slight thickening of the stratum corneum epidermis layer in the guinea pigs' skin. Conclusion: Together, these results indicate that the gel with P. sarmentosum is safe for application on the skin, but may lead to sensitization upon repeated application.