Background and objective: Although the association of wall shear stress (WSS) with coronary artery disease has been well studied, that of mechanical wall stress (MWS) is mainly overlooked. In this study, we performed in-silico artery-specific modeling to investigate the involvement of both MWS and WSS in coronary artery disease. Methods: Fifteen coronary arteries from five adult familial hypercholesterolemic pigs were imaged by coronary computed tomography angiography, intravascular ultrasound, and optical coherence tomography at three time points (3, 9, and 12 months). Local WSS and MWS in 3 mm/45° sectors were determined using artery-specific computational models. The relationship of WSS and MWS with wall thickness change (ΔWT) over time was statistically analyzed using Generalized Linear Mixed models. Results: A positive ΔWT was measured in all sectors, where plaque sectors presented a greater ΔWT rate compared to plaque-free sectors. In plaque-free sectors, low WSS was associated with a higher ΔWT rate (p < 0.001). In plaque sectors, high MWS was associated with a higher ΔWT rate (p < 0.05), where ΔWT rate was, although slightly, even greater in the plaque sectors with lipid-rich necrotic core (p < 0.05). Conclusions: Our results from in-silico coronary-specific models suggest that WSS and MWS may play a dominant role at different stages of coronary artery disease. WSS may be more critical in the early stages of plaque formation while MWS might have greater significance in the progression of existing plaques.