This study tested the hypothesis that the initial fall in arterial pressure evoked by lipopolysaccharide (LPS) is mediated by the ventrolateral column of the midbrain periaqueductal gray region (vlPAG). To test this hypothesis, the local anaesthetic lidocaine (2%; 0.1 μL, 0.2 μL or 1.0 μL), the delta opioid receptor antagonist naltrindole (2 nmol) or saline was microinjected into the vlPAG of isoflurane‐anaesthetized rats bilaterally and LPS (1 mg/kg) or saline was administered intravenously 2 min later. Both lidocaine and naltrindole inhibited LPS‐evoked hypotension significantly but did not affect arterial pressure in saline‐treated control animals. Neither lidocaine nor naltrindole altered heart rate significantly in either LPS‐treated or control animals. Microinjection of lidocaine or naltrindole into the dorsolateral PAG was ineffective. These data indicate that the vlPAG plays an important role in the initiation of endotoxic hypotension and further show that delta opioid receptors in the vlPAG participate in the response.