Recently, Maurya et al. (Ind. Eng. Chem. Res. 42 (2003b, c) 4789,4811) have presented a comprehensive framework for signed directed graph-based analysis of process systems where major theoretical results have been substantiated with simple examples or individual unit-based case studies. In this article, two case studies are presented to illustrate SDG-based analysis of process flowsheets containing many units and control loops. While the literature is replete with single unit examples, flowsheet level analysis as described in this paper is virtually non-existent. The first case study deals with prediction of initial response and its fault diagnostic application in the Tennessee Eastman (TE) flowsheet using a lumped parameter model of the process. The second case study deals with the steady-state analysis and fault diagnosis (FD) of a reaction–separation process. For this case study, the overall signed digraph for the process is developed from the digraphs for individual units and control loops in the flowsheet. It is shown that digraph-based steady-state analysis results in good diagnostic resolution.