This study evaluated the association between negative affective symptoms during initial abstinence and euphorigenic response to experimentally administered cocaine. Cocaine-dependent individuals achieved 5 days of abstinence in a hospital setting. Forty milligrams of cocaine was given intravenously on the fifth day of abstinence, and participants were asked to rate the subjective effects produced by the drug. The associations between irritability, self-reported depression, and the subjective "high" produced by cocaine were evaluated. Increased levels of irritability and depression both correlated positively and statistically significantly with heightened response to experimentally administered cocaine as indexed by self-reported subjective "high." The positive association between irritability and subjective "high" remained after controlling for self-reported depressive symptoms. The opponent process model predicts that increased levels of negative affect should be associated with diminished euphoric response to cocaine; however, the opposite was observed. If these findings are replicated in a larger sample, then it may be necessary to reconsider the applicability of the opponent process model to cocaine addiction in humans.