The present study investigated whether the outcome of randomized clinical trials studying fluoxetine favored fluoxetine, where this was the experimental agent, and favored comparator antidepressants in trials where fluoxetine was the reference agent. A systematic review of all double-blind, randomized clinical trials comparing fluoxetine with any other antidepressant drug in patients suffering from depression was carried out. Thirty-seven studies meeting the inclusion criteria were analyzed. A metaregression analysis indicated that, after adjusting for possible confounders, studies where fluoxetine was the experimental agent were positively associated with treatment effect, indicating a significant advantage for fluoxetine. The evidence that the outcome of fluoxetine trials varied according to whether this drug was used as a new compound or a reference one suggests the presence of bias.