Solder joint fatigue is a major concern in circuit board assemblies. A batch of FR4 test boards with different component layouts was assembled. These test boards were then put into an environmental chamber and subjected to thermal cycling. During the test, the samples were removed from the chamber at given intervals and examined by acoustic micro imaging. The solder joint reliability from origin to failure was obtained by processing these acoustic micro imaging data. The impact of different floor plans and component layouts on solder joint reliability were analysed. Remarkably, the results show that the floor plan and component layout have significant influence on solder joint reliability. Components placed in a mirrored configuration in a circuit board assembly have lower reliability than non-overlapping configurations and single-sided assembly. Finally, a stress-based finite element model with two simulation scenarios was carried out to correlate reliability findings with real experimental results.