Innocent suspects may not adequately protect themselves during interrogation because they fail to fully appreciate the danger of the situation. This experiment tested whether innocent suspects experience less stress during interrogation than guilty suspects, and whether refusing to confess expends physiologic resources. After experimentally manipulating innocence and guilt, 132 participants were accused and interrogated for misconduct, and then pressured to confess. Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), respiratory sinus arrhythmia (RSA), and preejection period (PEP) responses quantified stress reactions. As hypothesized, the innocent evidenced smaller stress responses to interrogation for SBP, DBP, HR, and RSA than did the guilty. Furthermore, innocents who refused to confess exhibited greater sympathetic nervous system activation, as evidenced by shorter PEPs, than did innocent or guilty confessors. These findings suggest that innocent suspects underestimate the threat of interrogation and that resisting pressures to confess can diminish suspects' physiologic resources and lead to false confessions.