To evaluate the chemical behavior and the health impact of welding fumes (WF), a complex and heterogeneous mixture of particulate metal oxides, two certified reference materials (CRMs) were tested: mild steel WF (MSWF-1) and stainless steel WF (SSWF-1). We determined their total chemical composition, their solubility, and their oxidative potential in a phosphate buffer (PB) solution under physiological conditions (pH 7.4 and 37 °C). The oxidative potential (OPDTT) of WF CRMs was evaluated using an acellular method by following the dithiothreitol (DTT) consumption rate (µmol DTT L−1 min−1). Pure metal salts present in the PB soluble fraction of the WF CRMs were tested individually at equivalent molarity to estimate their specific contribution to the total OPDTT. The metal composition of MSWF-1 consisted mainly of Fe, Zn, Mn, and Cu and the SSWF-1 composition consisted mainly of Fe, Mn, Cr, Ni, Cu, and Zn, in diminishing order. The metal PB solubility decreased from Cu (11%) to Fe (approximately 0.2%) for MSWF-1 and from Mn (9%) to Fe (<1%) for SSWF-1. The total OPDTT of SSWF-1 is 2.2 times the OPDTT of MSWF-1 due to the difference in oxidative capacity of soluble transition metals. Cu (II) and Mn (II) are the most sensitive towards DTT while Cr (VI), Fe (III), and Zn (II) are barely reactive, even at higher concentrations. The OPDTT measured for both WF CRMs extracts compare well with simulated extracts containing the main metals at their respective PB-soluble concentrations. The most soluble transition metals in the simulated extract, Mn (II) and Cu (II), were the main contributors to OPDTT in WF CRMs extracts. Mn (II), Cu (II), and Ni (II) might enhance the DTT oxidation by a redox catalytic reaction. However, summing the main individual soluble metal DTT response induces a large overestimation probably linked to modifications in the speciation of various metals when mixed. The complexation of metals with different ligands present in solution and the interaction between metals in the PB-soluble fraction are important phenomena that can influence OPDTT depletion and therefore the potential health effect of inhaled WF.