The large Derni Cu-Co (-Zn) deposit in Qinghai Province exhibits unusual geological features, and its genesis is controversial. Based on previous research and detailed field investigations, petrographic studies of the host volcanic rocks, isotope and trace element geochemistry of the sulfide ore, and comparison with typical ore deposits, this deposit is a VHMS (submarine volcanic-hosted massive sulfide deposit) type. This argues against previous interpretations of a magmatic or a hydrothermal replacement origin. Systematic rock, mineral and geochemical studies of the host serpentinites of the ore district indicate that the protoliths of several types of serpentinites that are widespread in the ore district are mainly ultramafic volcanic rocks. The mineralization formed within an ultramafic volcanic breccia, or between the breccia and its overlying Mg-rich carbonate rocks and volcanic sedimentary rocks. The ore-forming components were derived mainly from ultramafic rocks and partly from mafic rocks. The ultramafic rocks are MgO-rich, CaO-poor with a high MgO/FeO ratio, and the mafic rocks are rich in Na2O and poor in K2O. The chemical composition of the ultramafic rocks is similar to that of volcanic peridotite, or komatiite. The volcanic rocks that host the Derni deposit are among the most basic host rocks known for VHMS deposits, and the Derni deposit represents the most basic member in the VHMS deposit spectrum.