The building envelope design constrains how much HVAC systems must work to provide comfort. High thermal mass in walls is preferable to delay heat gain, as well as reduce it. Phase Change Materials (PCMs) seem to proportionate more thermal mass without increasing wall thickness because of their high latent heat. Thus, this work studies various PCM-based envelope layouts in four case studies, H060, H100, H200, and OB, under the tropical climate of Panama City, via building energy performance simulation. Energy and thermal comfort performance were used as criteria to determine an optimal PCM-based layout for such a climate through optimization analysis and to compare PCM-based and non-PCM-based envelope layouts. Results showed that among the considered combinations, PCM-based roof configurations provide more optimum solutions than PCM-based wall configurations. The PCM layout with a melting temperature of 27 °C allowed completion of the PCM cycle throughout the year. Although other PCM layouts did not present a complete charge/discharge cycle, such as the most frequent options at H060, H100, and H200, it suggests that PCM on liquid or solid phase provides better thermal performance than other considered combinations.