Although forensic proteomics is an emerging field, it remains underutilized as a tool for criminal investigations. Here we present its use in providing key evidence in an involuntary manslaughter case. The defendant was known to be a keeper of exotic snakes, including several venomous species, which led to a probe of potential snake venom components in the blood of the deceased. One major challenge of the investigation was the overwhelming presence of several blood proteins, such as albumin and immunoglobulins, which obscures the detection of less abundant ones. To mitigate this problem, proteins from the blood were processed in four different ways involving a combination of immunodepletion and fractionation methods, then prepared for peptide identification by mass spectrometry. We were able to sequence ~15,000 peptides, but another challenge was to differentiate between human and snake proteins, given the genetic similarities that are shared by the two species. After a thorough bioinformatics search and manual inspection, we found that <1% of the sequenced peptides were matched unequivocally to snake proteins, including a well-known venom component, phospholipase A2. This led to a court-issued search warrant of the defendant’s home, followed by his arrest and an eventual guilty plea with formal sentencing to 18 months in prison. The work outlined here is an example of proteomics technology that can help to expand the scope of forensic genetics.