Introduction: Reconstruction of large defects in the upper arm remains challenging due to insufficient tissue available, the tensions involved and anatomical limitations. Despite considerable donor site morbidity and technical difficulty, there are numerous techniques, including free and regional flaps, based on reliable and predictable anatomy. The introduction of perforator-based flaps has significantly led to reducing donor site morbidity. We aim to describe an approach combining a keystone type 1 flap and a synthetic skin substitute as a valid alternative for treating large upper arm defects. Materials and Methods: We report a case of a 67-year-old male who was adreessed to our department for melanoma wide excision on the posterior side of the upper left arm. Considering the significant size of the 14 x 8 cm defect and the good compliance of the patient, we decide to perform a multistage reconstruction. The first stage included a 1cm width safety margin surgical excision associated with axillary sentinel lymph node biopsy and a reconstruction based on the keystone type 1 flap with the temporary closure of the remaining tissue defect using a synthetic skin substitute. The second and third stages were performed one and two weeks later, respectively, and included removal of the temporary skin substitute and tension-free closure of the residual defect under local anaesthesia. Results: The recovery was uneventful with no surgical complications, and follow-up at 3-months postoperatively showed excellent aesthetic and functional outcomes. Conclusion: A combined approach based on keystone type 1 flap with a synthetic skin substitute can be used as a multistage procedure that allows reconstruction of large size defects of the upper arm. This is a viable option, especially for patients with good compliance. It provides optimal results while avoiding the donor site morbidity of other more challenging techniques.