The WHIM syndrome is a rare immunodeficiency disorder characterized by Warts, Hypogammaglobulinemia, Infections and Myelokathexis. Dominant heterozygous mutations of the gene encoding CXCR4, a G protein-coupled receptor with a unique ligand, CXCL12, have been associated with this pathology. We studied patients belonging to three different pedigrees. Two siblings inherited a CXCR4 mutation encoding a novel C-terminally truncated receptor. Two unrelated patients were found to bear a wild-type CXCR4 open reading frame. Circulating lymphocytes and neutrophils from all patients displayed similar functional alterations of CXCR4-mediated responses featured by a marked enhancement of G-protein dependent responses. This phenomenon relies on the refractoriness of CXCR4 to be both desensitized and internalized in response to CXCL12. Therefore, the aberrant dysfunction of the CXCR4-mediated signaling constitutes a common biological trait of WHIM syndromes with different causative genetic anomalies. Responses to other chemokines, namely CCL4, CCL5 and CCL21, were preserved, suggesting that in clinical forms associated with a wild-type CXCR4 open reading frame, the genetic anomaly might target an effector with some degree of selectivity for the CXCL12/CXCR4 axis. We propose that the sustained CXCR4 activity in patient cells accounts for the immune-haematological clinical manifestations and the profusion of warts characteristic of the WHIM syndrome.