When we compared the midgut proteomes of Drosophila melanogaster larvae fed diet containing 0.3% (w/w) of the Bowman Birk serine protease inhibitor (BBI) with those fed control diet, we observed fourteen differentially-expressed proteins. These were associated with the following enzymes or transport functions: sterol carrier protein X (SCPX), ubiquitin conjugating enzyme (E2-C), endopeptidase, electron transport, receptor signaling protein kinase, ATP-dependent RNA helicase, and -tocopherol transport. Using qRT-PCR we verified that dietary BBI causes differential expression of twelve genes that encode these proteins. It appears that BBI affects expression of proteins associated with protein degradation and transport as well as fatty acid catabolism. The midgut tissue in BBI-fed Drosophila appears to be responding as if it were injured. Inhibition of one of the BBI-elevated proteins, SCPX, resulted in the insects becoming more susceptible to the negative effects of dietary BBI.