This study tested for alpha-2 adrenergic mediation of the inverse relationship between resting blood pressure and acute pain sensitivity in healthy individuals. It also replicated limited prior work suggesting this inverse blood pressure/pain association is altered in chronic pain, and provided the first test of whether chronic pain-related changes in alpha-2 adrenergic function contribute to these alterations. Resting blood pressure was assessed in 32 healthy controls and 24 chronic low back pain participants prior to receiving placebo or an intravenous alpha-2 adrenergic receptor antagonist (yohimbine hydrochloride, 0.4 mg/kg) in a randomized crossover design. Participants experienced three acute pain tasks during both sessions. A significant Systolic Blood Pressure x Participant Type x Drug interaction on finger pressure McGill Pain Questionnaire-Sensory ratings (P < .05) reflected significant hyperalgesic effects of yohimbine in chronic pain participants with lower systolic blood pressures (P < .05) but not those with higher systolic pressures, and no significant effects of yohimbine in controls regardless of blood pressure level. A Drug x Systolic Blood Pressure interaction on finger pressure visual analog scale unpleasantness indicated the inverse blood pressure/pain association was significantly stronger under yohimbine relative to placebo (P < .05). Significant Participant Type x Systolic Blood Pressure interactions (P's < .05) were noted for finger pressure visual analog scale pain intensity and unpleasantness, ischemic pain threshold, and heat pain threshold, reflecting absence or reversal of inverse blood pressure/pain associations in chronic pain participants. Results suggest that blood pressure-related hypoalgesia can occur even when alpha-2 adrenergic systems are blocked. The possibility of upregulated alpha-2 adrenergic inhibitory function in chronic pain patients with lower blood pressure warrants further evaluation.