Better prognostic predictors for invasive candidiasis (IC) are needed to tailor and individualize therapeutic decisionmaking and minimize its high morbidity and mortality. We investigated whether molecular profiling of IgG-antibody response to the whole soluble Candida proteome could reveal a prognostic signature that may serve to devise a clinical-outcome prediction model for IC and contribute to known IC prognostic factors. By serological proteome analysis and data-mining procedures, serum 31-IgG antibody-reactivity patterns were examined in 45 IC patients randomly split into training and test sets. Within the training cohort, unsupervised two-way hierarchical clustering and principal-component analyses segregated IC patients into two antibody-reactivity subgroups with distinct prognoses that were unbiased by traditional IC prognostic factors and other patients-related variables. Supervised discriminant analysis with leave-one-out cross-validation identified a five-IgG antibody-reactivity signature as the most simplified and accurate IC clinical-outcome predictor, from which an IC prognosis score (ICPS) was derived. Its robustness was confirmed in the test set. Multivariate logistic-regression and receiver-operating-characteristic curve analyses demonstrated that the ICPS was able to accurately discriminate IC patients at high risk for death from those at low risk and outperformed conventional IC prognostic factors. Further validation of the five-IgG antibody-reactivity signature on a multiplexed immunoassay supported the serological proteome analysis results. The five IgG antibodies incorporated in the ICPS made biologic sense and were associated either with good-prognosis and protective patterns (those to Met6p, Hsp90p, and Pgk1p, putative Candida virulence factors and antiapoptotic mediators) or with poor-prognosis and risk patterns (those to Ssb1p and Gap1p/Tdh3p, potential Candida proapoptotic mediators). We conclude that the ICPS, with additional refinement in future larger prospective cohorts, could be applicable to reliably predict patient Despite recent advances in antifungal therapy, invasive candidiasis (IC) 1 remains a leading infectious cause of morbidity and mortality in cancer, postsurgical, and intensive care patients (1-3). Its significant impact on patient clinical outcome, as reflected in its increased attributable mortality (10%-49%), length of hospital stay (3-30 days per patient), and healthcare costs (US $ 6214 -92,266 per episode), could however be ameliorated if early and appropriate antifungal therapeutic strategies were administered (1, 4). This precondition highlights the need to search for prognostic features that may reliably predict the clinical outcome in IC patients at presentation to tailor and individualize therapeutic decision-making accordingly and, as a result, to minimize the burden of the invasive infections caused by Candida spp. (commonly Candida albicans (1)).Several factors have classically been reported to adversely influence the clinical outcome of IC patients (3, ...