The reliability of solder joints in flip chip assemblies with both compliant (flex) and rigid (PCB) substrates was studied by accelerated temperature cycling tests and finite element modeling (FEM). In-process electrical resistance measurements and nondestructive evaluations were conducted to monitor solder joint failure behavior, hence the fatigue failure life. Meanwhile, the predicted fatigue failure life of solder joints was obtained by Darveaux’s crack initiation and growth models. It can be concluded that the solder joints in flip chip on flex assembly (FCOF) have longer fatigue life than those in flip chip on rigid board assembly (FCOB); the maximum von Mises stress/strain and the maximum shear stress/strain of FCOB solder joints are much higher than those of FCOF solder joints; the thermal strain and stress in solder joints is reduced by flex buckling or bending and flex substrate could dissipate energy that otherwise would be absorbed by solder joint. Therefore, the substrate flexibility has a great effect on solder joint reliability and the reliability improvement was attributed to flex buckling or bending during temperature cycling.