Background: Proteins control and mediate many biological activities of cells by interacting with other protein partners. This work presents a statistical model to predict protein interaction networks of Drosophila melanogaster based on insight into domain interactions. Results: Three high-throughput yeast two-hybrid experiments and the collection in FlyBase were used as our starting datasets. The co-occurrences of domains in these interactive events are converted into a probability score of domaindomain interaction. These scores are used to infer putative interaction among all available open reading frames (ORFs) of fruit fly. Additionally, the likelihood function is used to estimate all potential protein-protein interactions. All parameters are successfully iterated and MLE is obtained for each pair of domains. Additionally, the maximized likelihood reaches its converged criteria and maintains the probability stable. The hybrid model achieves a high specificity with a loss of sensiti...