Objective: Cellular sensitivity to heat is highly variable depending on the cell line. The aim of this paper is to assess the cellular sensitivity of the A375 melanoma cell line to continuous (CW) millimeter-waves (MMW) induced heating at 58.4 GHz, between 37 C and 47 C C to get a deeper insight into optimization of thermal treatment of superficial skin cancer. Methods: Phosphorylation of heat shock protein 27 (HSP27) was mapped within an area of about 30 mm2 to visualize the variation of heat-induced cellular stress as a function of the distance from the waveguide aperture (MMW radiation source). A multiphysics computational approach was then adopted to yield both electromagnetic and thermal field distributions as well as corresponding specific absorption rate (SAR) and temperature elevation. Induced temperature rise was experimentally measured using a micro-thermocouple (TC). Results: Coupling of the incident electromagnetic (EM) field with TC leads was first characterized, and optimal TC placing was identified. HSP27 phosphorylation was induced at temperatures 41 C, and its level increases as a function of the thermal dose delivered, remaining mostly focused within 3 mm2. Conclusion: Phosphorylation of HSP27 represents a valuable marker of cellular stress of A375 melanoma cells under MMW exposure, providing both quantitative and spatial information about the distribution of the thermal stress. Significance: These results may contribute to the design of thermal treatments of superficial melanoma through MMW-induced heating in the hyperthermic temperature range.