A comprehensive model-based thermo-hydraulic methodology is used to investigate fouling behaviour in refinery heat exchangers where high concentration of inorganics in the deposits was reported. The method combines a data-driven analysis of plant measurements (including pressure drop) with a model-based analysis using advanced models of shell-and-tube heat exchangers undergoing fouling. A deposit model capable of tracking composition and deposition history was extended to include thermal-conductivity mixing models appropriate for various deposit structures. Substantial new and useful information can be extracted from the plant measurements in comparison to current practice: the thickness, the effective conductivity, and the radial conductivity and composition profiles of the deposits, reflecting the exchanger operation history. Episodes of rapid and acute fouling, and deposition of inorganic materials could be identified and quantified. A validation of the approach was carried out by (i) a comparison of averaged predicted and experimental inorganic weight fractions in a mixed deposit sample collected at the end of run, and (ii) an initial comparison of predicted radial inorganics profiles and experimental ones (obtained with SEM-EDX) in deposits from similar exchangers. Both steps yielded surprisingly good agreement. The study indicates that the method employed represents a new powerful, model-based analysis tool for monitoring, diagnosis and troubleshooting of fouling in heat exchangers.