Serine protease inhibitors have therapeutic potential in a variety of pathogenic processes, ranging from thrombosis, altered immune response to liver cirrhosis. To investigate the physiological effects of protein C inhibitor (PCI, serpinA5) this gene was inactivated in a mouse model with the resulting phenotype of male infertility. In the actual report 2D-DIGE analysis was utilized to investigate the molecular mechanisms for PCI in male reproduction. Comparing the testes proteome of three PCI knockout-mice with the three wild-types- demonstrated similar pattern with the exception of a massive upregulation of prostaglandin reductase 1 (10-fold; P < 0.002) and complete shifts in the molecular weights of serpinA1C and serpinA3K. All these PCI-dependent proteome changes were immunologically verified. Unbiased proteome analysis indicated that the inactivation of serpinA5 strongly influenced both the protein species pattern of other A-clade serpins as well as the prostaglandin metabolism in the testes.