Rationale: The role of ethanol-derived acetaldehyde has not been examined yet on performance in a model of operant oral self-administration. However, previous studies reported that an acetaldehyde-sequestering agent, D-penicillamine (DP) and an inhibitor of catalase-mediated acetaldehyde production, 3-amino-1,2,4-triazole (3-AT) reduce voluntary ethanol consumption. Objectives: The aim of our investigation was to evaluate the effects of DP and 3-AT on acquisition and maintenance of oral operant ethanol self-administration. Methods: Using operant chambers, rats learned to nose poke in order to receive ethanol solution (5-10% v/v) under a FR1 schedule of reinforcement in which discrete light and tone cues were presented during ethanol delivery. Results: DP and 3-AT impair the acquisition of ethanol self-administration, whereas its maintenance is not affected by neither drug given alone, for both 10 or 5% ethanol, nor by drugs association for 5% ethanol. Moreover, when the concentration of ethanol was diminished from 10 to 5 %, rats increased the rate of self-administration behaviour. Conclusions: These findings suggest that brain acetaldehyde plays a critical role during acquisition of operant self-administration in ethanol-naïve rats. In contrast, during the maintenance phase acetaldehyde could contribute to ethanol self-administration by a combined mechanism: on one hand its lack (by DP or 3-AT) might result in further ethanol-seeking and taking and, on the other, inhibition of ethanol metabolism (by 3-AT) might release an action of the un-metabolized fraction of ethanol that does not overall result in compromising maintenance of ethanol self-administration.