Purpose: We aimed to determine the in-vitro diagnostic performance of multi-energy spectral photon-counting CT (SPCCT) in crystal-related arthropathies. Methods: Four crystal types (monosodium urate, MSU; calcium pyrophosphate, CPP; octacalcium phosphate, OCP; and calcium hydroxyapatite, CHA) were synthesized and blended with agar at the following concentrations: 240, 88, 46, and 72 mg/mL, respectively. Crystal suspensions were scanned on a pre-clinical SPCCT system at 80 kVp using the following four energy thresholds: 20, 30, 40, and 50 keV. Differences in linear attenuation coefficients between the various crystal suspensions were compared using the receiver operating characteristic (ROC) paradigm. Areas under the ROC curves (AUC), sensitivities, specificities, and diagnostic accuracies were calculated. Crystal differentiation was considered successful if AUC>0.95. Results: For each paired comparison of crystal suspensions, AUCs were significantly higher in the first energy range (20-30 keV). In the first energy range, MSU was confidently differentiated from CPP (sensitivity, 0.978; specificity, 0.990; accuracy, 0.984) and CHA (sensitivity, 0.957; specificity, 0.970; accuracy, 0.964), while only moderately distinguished from OCP (sensitivity, 0.663; specificity, 0.714; accuracy, 0.688). CPP was confidently differentiated from OCP (sensitivity, 0.950; specificity, 0.954; accuracy, 0.952), while only moderately from CHA (sensitivity, 0.564; specificity, 0.885; accuracy, 0.727). OCP was accurately differentiated from CHA (sensitivity, 0.898; specificity, 0.917; accuracy, 0.907). Conclusions: Multi-energy SPCCT can accurately differentiate MSU from CPP and CHA, CPP from OCP, and OCP from CHA in vitro. The distinction between MSU and OCP, and CPP and CHA is more challenging.