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Epidermal energy metabolism is relevant to skin physiology, ageing and photodamage. While selected hormones stimulate epidermal keratinocyte mitochondrial activity, its negative regulation remains unknown. In several cell types, cannabinoid receptor 1 (CB1 ) is expressed both on the cell membrane (cmCB1 ) and on the mitochondrial outer membrane (mtCB1 ), where its stimulation directly suppresses mitochondrial functions. In the current pilot study, we investigated if CB1 is a negative regulator of human epidermal energy metabolism under physiological conditions. Using organ-cultured full-thickness human skin specimens of healthy individuals, we showed that antagonizing the homeostatic CB1 signalling by the administration of the CB1 inverse agonist AM251 increased respiratory chain complex I and II/IV activity. The effect was CB1 -dependent, since the CB1 -selective agonist arachidonyl-2'-chloroethylamide could prevent the effect. Moreover, the phenomenon was also reproduced by siRNA-mediated down-regulation of CB1 . As revealed by the unaltered expression of several relevant markers (TFAM, VDAC1, MTCO1 and NDUFS4), modulation of CB1 signalling had no effect on the epidermal mitochondrial mass. Next, by using immunoelectron microscopy, we found that human epidermal keratinocytes express both cmCB1 and mtCB1 . Finally, by using equipotent extracellularly restricted (hemopressin) as well as cell-permeable (AM251) inverse agonists, we found that mitochondrial activity is most likely exclusively regulated by mtCB1 . Thus, our data identify mtCB1 as a novel negative regulator of keratinocyte mitochondrial activity in intact human epidermis, and raise the question, whether topical therapeutic interventions capable of selectively activating mtCB1 can reduce excessive mitochondrial ROS production resulting from dysregulated mitochondrial activity during skin ageing or photodamage.