Fixed-bed resid desulfurization (RDS) is an important industrial catalytic process to produce low sulfur fuel oil and to pretreat feed for resid fluid catalytic cracking (RFCC) unit. The catalytic system is based on a complex stacking of task-specific catalysts. To improve the RDS performances, it is crucial to better understand and monitor the nature and amount of contaminants (especially sulfur and metals) along the process. In the present paper, an hyphenated technique based on Size Exclusion Chromatography separation (SEC) and Inductively-Coupled Plasma/Mass Spectrometry (ICP/MS) detection is applied to develop an innovative quantitative method: it allows to quantify the refractory compounds related to their molecular size. The analysis of the effluents arising from the different catalyst beds demonstrates the selectivity of each catalyst toward the molecular size of sulfur and vanadium containing molecules.