Failure analysis is an important part of realizing the growth of machining center reliability level, so it is important to improve the accuracy of failure analysis. In view of this, this paper first considered the relationship and influence among failure subsystem elements of machining center, constructed the hierarchical structure model based on ISM method, made clear the class of interrelated failure subsystem, found out the deep failure subsystem elements and determined the weak link in the reliability improvement. Secondly, it analyzed the subsystem with FMECA, and determined the critical failure modes of the subsystem and laid a foundation for improving the reliability of machining center. Finally, it did the case study based on the field failure data of a series of machining center. The result has proved that the above method is accurate and effective in the failure analysis of machining center.