Ultramafic-hosted volcanogenic massive sulfide deposits (UM-VMS) located in the Havana-Matanzas ophiolite (Cuba) are the only known example of this type of mineralization in the Caribbean realm. UM-VMS from Havana-Matanzas are enriched in Cu, Ni, Co, Au, and Ag. The mineralization consists of massive sulfide bodies mostly composed of pyrrhotite and hosted by serpentinized upper mantle peridotites. Chemical composition of unaltered cores in Cr-spinel grains found within the massive sulfide mineralization and in the peridotite host indicates formation in the fore-arc region of the Greater Antilles volcanic arc. A first stage of serpentinization probably took place prior to the sulfide mineralization event. The UM-VMS mineralization formed by the near-complete replacement of the silicate assemblage of partially serpentinized peridotites underneath the seafloor. The sequence of sulfide mineralization has been divided into two stages. The first stage is characterized by a very reduced hydrothermal mineral assemblage consisting of pyrrhotite, Co–Ni–Fe diarsenides, chalcopyrite, Co-rich pentlandite, and electrum. In the second stage, pyrite and Co–Ni–Fe sulfarsenides partially replaced pyrrhotite and diarsenides, respectively, under a more oxidizing regime during the advanced stages of ongoing serpentinization. The proposed conceptual genetic model presented here can be useful for future exploration targeting this type of deposit in the Caribbean region and elsewhere.