BACKGROUND: To address the limitations of traditional virus and pathogen detection methodologies in clinical diagnosis, scientists have developed high-throughput oligonucleotide microarrays to rapidly identify infectious agents. However, objectively identifying pathogens from the complex hybridization patterns of these massively multiplexed arrays remains challenging. METHODS: In this study, we conceived an automated method based on the hypergeometric distribution for identifying pathogens in multiplexed arrays and compared it to five other methods. We evaluated these metrics: 1) accurate prediction, whether the top ranked prediction(s) match the real virus(es); 2) four accuracy scores. RESULTS: Though accurate prediction and high specificity and sensitivity can be achieved with several methods, the method based on hypergeometric distribution provides a significant advantage in term of positive predicting value with two to sixty folds the positive predicting values of other methods. CONCLUSION: The proposed multi-specie array analysis based on the hypergeometric distribution addresses shortcomings of previous methods by enhancing signals of positively hybridized probes.