Assignment of putative protein functional annotation by comparative analysis using pre-defined experimental annotations is performed routinely by molecular biologists. The number and statistical significance of these assignments remains a challenge in this era of high-throughput proteomics. A combined statistical method that enables robust, automated protein annotation by reliably expanding existing annotation sets is described. An existing clustering scheme, based on relevant experimental information (e.g. sequence identity, keywords or gene expression data) is required. The method assigns new proteins to these clusters with a measure of reliability. It can also provide human reviewers with a reliability score for both new and previously classified proteins.