This study reports new geochemical and Sr-Nd-Pb radiogenic isotope data on hy-normative Quaternary basaltic to rhyolitic volcanic rocks as well as two samples of Mesozoic to Palaeozoic intrusive igneous rocks from Los Humeros caldera (LHC), located in the eastern part of the Mexican Volcanic Belt (MVB). The isotopic ratios of mafic basaltic rocks range as follows: 8 7 Sr/ 8 6 Sr=0.703350-0.703387, 1 4 3 Nd/ 1 4 4 Nd=0.512867-0.512888, 2 0 6 Pb/ 2 0 4 Pb=18.849-18.866, 2 0 7 Pb/ 2 0 4 Pb=15.593-15.598, and 2 0 8 Pb/ 2 0 4 Pb=38.490-38.491. These values are similar to the rift-related mafic rocks from the volcanic front of the central MVB. For comparison, the entire suite from basalt (B) to rhyolite (R) in the LHC shows the following ranges. 8 7 Sr/ 8 6 Sr=0.703350-0.704678, 1 4 3 Nd/ 1 4 4 Nd=0.512702-0.512888, 2 0 6 Pb/ 2 0 4 Pb=18.710-18.866, 2 0 7 Pb/ 2 0 4 Pb=15.593-15.631, and 2 0 8 Pb/ 2 0 4 Pb=38.444-38.594. The basaltic rocks from Los Humeros do not show the characteristic negative Nb anomaly with respect to Ba and Ce, as is typical of such magmas in volcanic arcs. The available geochemical and isotopic evidence does not support the generation of the LHC mafic magmas by direct (slab melting), nor by indirect (fluid transport to the mantle) participation of the subducted Cocos plate. Instead, they could be generated in the upper mantle from a lithospheric source. The evolved andesitic to rhyolitic magmas could have been originated from such mafic magmas through assimilation coupled with extensive fractional crystallisation. Two different compositions representing lower (LC) and upper crusts (UC) as well as a hypothetical crust (HA) were tested as plausible assimilants for the assimilation coupled with fractional crystallisation process.