We previously reported an association between dopamine receptor D4 (DRD4) gene exon 1 variants and delusional disorder. The aim of this investigation was to study the DRD4 gene exon 1 and 3 variants in schizophrenia, delusional, bipolar, and unipolar disorders. We studied 651 inpatients affected by schizophrenia (n = 229), delusional (n = 86), bipolar (n = 210), and unipolar (n = 126) disorders (DSM III-R) and 471 healthy controls; these were typed for DRD4 variants at the first and third exon using polymerase chain reaction techniques. DRD4 variants were not associated with schizophrenic and delusional subjects even when possible confounders like gender and onset were considered. A marginal association between DRD4 exon 3 variants with unipolar (excess of DRD4*2/4, p = 0.004) and bipolar (excess of DRD4*2/4, p = 0.001) disorders was observed, both associations drop to insignificance when corrected for multiple testing. Our results exclude that coding variants of the DRD4 exon 1 and 3 may play a major role in conferring susceptibility to major psychoses; moreover, we could not replicate the association of DRD4 exon 1 variant with delusional disorder.