Inhibition or modulation of the human complement system has long been considered a target for therapeutic intervention given complement’s central role in numerous inflammatory and autoimmune diseases. In particular, complement activation plays an essential role in ischemia-reperfusion (IR) injury in such conditions as myocardial infarction, stroke, organ transplantation rejection as well as other clinical disorders. While current complement inhibitory strategies have focused on downstream components C3, C5 and soluble complement regulators, inhibition of the initiator molecules of the classical and lectin pathways of complement, C1q and MBL (mannose binding lectin), respectively, have not been vigorously pursued. Previous studies have highlighted the critical role of C1 and MBL activation in initiating IR injury, thus inhibition of these molecules represents a viable therapeutic option for prevention of IR-mediated tissue damage. We have recently discovered a peptide originally derived from a viral capsid protein that has been demonstrated to potently inhibit C1 and MBL activation via a novel mechanism of action. In this review, we examine the role of the classical and lectin complement pathway activation in IR injury and the potential of this unique peptide inhibitor as an anti-complement therapeutic for use in IR disease. In view of the well-defined role of C1 and MBL activation in IR injury and the ability of this peptide to inhibit complement activation early at the point of initiation, this molecule provides a unique opportunity to halt complement activation in its tracks before amplification of the complement cascade and the commencing of inflammatory responses.