The six studied southwestern Colombian Plio-Quaternary volcanoes (Puracé, Doña Juana, Galeras, Azufral, Cumbal and Chiles) are located in the central part of the Northern Volcanic Zone (NVZ) of the Andes. The lavas are predominantly andesites and dacites, with lesser amount of basalt, and range 52% to 70% SiO₂. The two-pyroxenes basic and acid andesites exhibit plagioclase phenocrysts with core composition of An50–80 and An40–70 respectively. Hornblende and biotite occur in dacites in association with plagioclase cores ranging An30–50. The lavas belong to medium- to high-potassic calc-alkaline series, typical of active continental margins. Two types of lavas can be distinguished in the studied area: 1) Northeastern-type lavas which show high TiO₂, K-group elements, LREE, and Ce/Yb ratio, low HREE content and a low Ba/La ratio 2) Southwestern-type lavas are characterized by low TiO₂, K-group elements, LREE, low Ce/Yb, an enrichment in HREE content and high Ba/La ratio. The northward increase in incompatible elements is attributed to a higher contribution of the siliceous Pre-Mesozoic crust in the north of the studied area. The younger (Post-Cretaceous) oceanic basement underlying the southwestern volcanoes cannot be responsible for an enrichment in incompatible elements only by contamination processes. Geochemical evidences suggest that the NVZ calc-alkaline lavas were derived from a primitive mantle which was enriched in Ba and partially in other K-group elements by dehydration and/or partial melting of the oceanic slab within the asthenosphere. This primitive melt, induced in response of the hydration processes within the mantle, suffered various stages of assimilation and fractional crystallization at lower to intermediate crustal levels, as revealed by the regional depletion in HREE of the northeastern-type lavas. At an upper crustal level, within the magma chamber, magma mixing between “primitive” up-rising basalt melt and andesitic-dacitic differentiated magma accompanied by fractional crystallization and crustal assimilation processes produced the andesitic series of each volcanoes.