Aims: Investigation of changes in the protein profile of the wood-rot fungus, Schizophyllum commune when paired against the biocontrol fungus, Trichoderma viride for 48 hours. Methods and Results: Variations in protein profile resulting from contact with T. viride were assessed by spot separation using 2-Dimensional protein gel electrophoresis followed by MALDI-TOF-TOF MS/MS protein identification. Contact with T. viride elicited a systematic response by S. commune, characterized by marked increases in proteins involved in transcription and translation (61%) and cell wall/hyphal biogenesis and stabilisation (17%), whereas metabolism-associated proteins decreased in amounts (64%). T. viride however, exhibited typical mycoparasitic behaviour with increases in the amounts of proteins involved in proteolysis and carbohydrate metabolism. Conclusions: The protein profile of S. commune confronted by T. viride indicates the up-regulation of mechanisms specifically targeted at the mycoparasitic machinery of T. viride particularly cell wall lysis and antibiosis. Significance and Impact of the Study: The proteomic responses observed in S. commune may occur in natural environments, providing an insight to the mechanism involved in conferring resistance to mycoparasitic attack. This study therefore, warrants further investigation for the targeted design of more robust biocontrol agents. © 2012 The Authors Letters in Applied Microbiology © 2012 The Society for Applied Microbiology.