Increasing use of oleoresin capsicum (OC) spray devices (i.e., pepper spray, pepper mace, OC, capsaicin) by law enforcement agencies as a means of sublethal force to control suspects has brought into question whether exposure to this noxious irritant (capsaicin) can cause or contribute to unexpected in-custody deaths. Capsaicin stimulates nociceptors in exposed mucous membranes to produce intense pain, particularly involving the conjunctiva, and generates systemic physiologic and behavioral responses consonant with such extreme discomfort. We describe two cases of in-custody death, both associated temporally with the use of pepper spray, to illustrate salient investigative considerations. As with any other in-custody death, a thorough autopsy and toxicologic analysis, coupled with evaluation of the premortem chain of events, postexposure symptomatology, and the extent of natural disease processes, will help to reveal the role of oleoresin capsicum spray as unrelated, contributory, or causative.