Case reports indicate that antipsychotics can cause priapism, a persistent penile erection possibly leading to erectile dysfunction. The mechanism of antipsychotic-induced priapism is thought to be related to blockade of alpha1 adrenergic receptors, but clinical data supporting this hypothesis are lacking. The aim of this study was to investigate if the presence of safety signals for antipsychotics and priapism is associated with their alpha1 affinity. Spontaneous reports of adverse drug reactions contained in the US Adverse Event Reporting System database were used to calculate reporting odds ratios (RORs) of priapism for antipsychotics. In total, 426 cases of priapism with 144 of them attributed to antipsychotics were identified. For antipsychotics with high alpha1 affinity, the adjusted ROR was markedly elevated (ROR = 9.9; 95% CI, 7.9-12.4), whereas a weaker signal was observed for antipsychotics with low/medium alpha1 affinity (ROR = 3.6; 95% CI, 2.4-5.2). Signals were present for chlorpromazine, quetiapine, risperidone, ziprasidone, and aripiprazole. After restricting the analysis to cases with medical intervention or disability, the safety signal remained evident only for antipsychotics with high but not for those with low/medium affinity. The observed pattern of signals indicates a relationship between alpha1 affinities of antipsychotics and the occurrence of priapism.