This paper investigates the challenging problem of diagnosing novel faults whose fault mechanisms and relevant historical data are not available. Most existing fault diagnosis systems are incapable to explain root causes for unanticipated, novel faults, because they rely on either models or historical data of known faulty conditions. To address this issue we propose a new framework for novel fault diagnosis, which integrates causal reasoning on signed digraph models with multivariate statistical process monitoring. The prerequisites for our approach include historical data of normal process behavior and qualitative cause-effect relationships that can be derived from process flow diagrams. In this new approach, a set of candidate root nodes is identified first via qualitative reasoning on signed digraph; then quantitative local consistency tests are implemented for each candidate based on multivariate statistical process monitoring techniques; finally, using the resulting multiple local residuals, diagnosis is performed based on the exoneration principle. The cause-effect relationships in the digraph enable automatic variable selection and the local residual interpretations for statistical monitoring. The effectiveness of this new approach is demonstrated using numerical examples based on the Tennessee Eastman process data. (C) 2012 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.