The purpose of this paper is to investigate the feasibility of a novel four-material decomposition technique for assessing the vulnerability of plaque with two contrast materials spectral computer tomography (CT) using two independent markers: plaque's inflammation and spotty calcification. A simulation study was conducted using an energy-sensitive photon-counting detector for k-edge imaging of the coronary arteries. In addition to detecting the inflammation status, which is known as a biological marker of a plaque's vulnerability, we use spotty calcium concentration as an independent marker to test a plaque's vulnerability. We have introduced a new method for detecting and quantifying calcium concentrations in the presence of two contrast materials (iodine and gold), calcium and soft tissue background. In this method, four-material decomposition was performed on a pixel-by-pixel basis, assuming there was an arbitrary mixture of materials in the voxel. The concentrations of iodine and gold were determined by the k-edge material decomposition based on the maximum likelihood method. The calibration curves of the attenuation coefficients, with respect to the concentrations of different materials, were used to separate the calcium signal from both contrast materials and different soft tissues in the mixtures. Three different materials (muscle, blood and lipid) were independently used as soft tissue. The simulations included both ideal and more realistic energy resolving detectors to measure the polychromatic photon spectrum in single slice parallel beam geometry. The ideal detector was used together with a 3 cm diameter digital phantom to demonstrate the decomposition method while a more realistic detector and a 33 × 24 cm(2) digital chest phantom were simulated to validate the vulnerability assessment technique. A 120 kVp spectrum was generated to produce photon flux sufficient for detecting contrast materials above the k-edges of iodine (33.2 keV) and gold (80.7 keV). By performing simulations on a 3 cm diameter digital phantom, we successfully identified four materials that were simultaneously present in the mixture at different proportions and in multiple locations on the phantom. Quantitative analysis with a chest digital phantom showed that the results for iodine, gold and calcium were highly correlated with the known concentrations. The analysis revealed a potentially powerful technique for assessing a plaque's vulnerability with two independent markers. High correlation and low relative errors between calculated and known materials' concentrations showed that the method is feasible. This technique can potentially have a high clinical impact.