The effects of 100 mg of intranasal cocaine (COC) in acute alcohol intoxication (1 g/kg) was assessed in nine experienced and non-dependent healthy volunteers in a double-blind, controlled, randomized, cross-over clinical trial. Alcohol alone impaired psychomotor performance, whereas COC alone produced subjective effects related to euphoria and well-being, improved the reaction time and increased heart rate and blood pressure. The combination of COC and alcohol induced a nonsignificant decrease in the subjective feelings of drunkeness, an increase in COC-induced euphoria, a significant improvement in alcohol-related changes in psychomotor performance and a marked increase in heart rate. Subjects experienced subjective and performance effects that could be self-interpreted as more pleasant compared to the effects of alcohol alone. When alcohol was given simultaneously, COC plasma levels were higher (possibly as a result of an inhibition of hepatic metabolism of COC produced by alcohol), norcocaine plasma levels almost doubled and cocaethylene was detected in plasma, so that its basic pharmacokinetic profile could be described. The simultaneous use of both drugs produced changes in heart rate and blood pressure that could increase the risk of cardiovascular toxicity associated with the use of COC.