BACKGROUND : The advent of high-throughput experimental techniques paved the way to genome-wide computational analysis and predictive annotation studies. When considering the joint annotation of a large set of related entities, like all proteins of a certain genome, many candidate annotations could be inconsistent, or very unlikely, given the existing knowledge. A sound predictive framework capable of accounting for this type of constraints in making predictions could substantially contribute to the quality of machine-generated annotations at a genomic scale. RESULTS : We present OCELOT, a predictive pipeline which simultaneously addresses functional and interaction annotation of all proteins of a given genome. The system combines sequence-based predictors for functional and protein-protein interaction (PPI) prediction with a consistency layer enforcing (soft) constraints as fuzzy logic rules. The enforced rules represent the available prior knowledge about the classification task, including taxonomic constraints over each GO hierarchy (e.g. a protein labeled with a GO term should also be labeled with all ancestor terms) as well as rules combining interaction and function prediction. An extensive experimental evaluation on the Yeast genome shows that the integration of prior knowledge via rules substantially improves the quality of the predictions. The system largely outperforms GoFDR, the only high-ranking system at the last CAFA challenge with a readily available implementation, when GoFDR is given access to intra-genome information only (as OCELOT), and has comparable or better results (depending on the hierarchy and performance measure) when GoFDR is allowed to use information from other genomes. Our system also compares favorably to recent methods based on deep learning.