Discontinuities with different joint wall strengths (DDJS) are very common in the Three Gorges reservoir area, P.R. China. Experimental results illustrate that the peak shear strength of DDJS is different from the discontinuities with identical joint wall strength (DIJS). However, few criteria are available in the literature to predict the peak shear strength of DDJS. In the present study, a new parameter “joint wall strength difference coefficient (JSC)” is introduced to quantify the comprehensive effects of rock tensile strength and joint basic friction angle on the peak shear strength of DDJS. The smaller JSC is, the greater the strength difference in the two joint walls is. The peak shear strengths of DDJS increase nonlinearly with the increase in JSC for the three groups of joint under each normal stress level, which can be effectively fitted by a simple logarithmic function. However, the normalized peak shear strength of DDJS is mainly controlled by roughness and strength difference. New empirical peak shear strength criterion is further developed by multivariate regression analysis, which is further validated by laboratory tests on natural rock joints. The good agreement between predicted values and experimental results illustrates that the developed criterion is capable of evaluating the peak shear strength of DDJS to some extent. Finally, the advantages and limitations of the new criterion are analyzed.