We determined whether the gas carbon monoxide (CO) altered the adrenocorticotropin hormone (ACTH) response to mild inescapable electrofootshocks, and whether it interacted with nitric oxide (NO). Peripheral injection of the NO synthase (NOS) inhibitor Nwnitro‐l‐arginine‐methylester (l‐NAME), a compound which readily crosses the blood–brain barrier, produced the expected blunting of the ACTH response to the shocks. This effect was mimicked by other arginine analogues such as l‐nitroarginine (l‐NNA) and NG‐methyl‐l‐arginine (NMMA). The subcutaneous (s.c.) administration of the heme oxygenase (HO) blockers tin mesoporphyrin (SnMP) or tin protoporphyrin (SnPP) significantly decreased brain HO levels, indicating that both compounds had penetrated the brain. Blood pressure showed a modest increase in response to SnMP, and no change after SnPP. SnMP and SnPP both decreased shock‐induced ACTH release, though the magnitude of this effect was slightly less than that of l‐NAME. The influence of SnPP was further augmented in rats with concomitant blockade of NO formation, which suggests that both NO and CO are necessary for the full response of this axis to electrofootshocks. Finally, the ability of SnPP to significantly blunt the expression of the mRNA for the immediate early gene NGFI‐B in the paraventricular nucleus (PVN) of rats exposed to shocks, indicates that the influence of CO was exerted on hypothalamic neuronal activity. Collectively, our results show that NO and CO exert a stimulatory effect on the HPA axis response to mild electrofootshocks, and that at least part of this influence takes place on hypothalamic neurons and/or their afferents.