A C825T polymorphism has been described in the GNB3 gene which encodes the Gbeta3 subunit of heterotrimeric G proteins. The GNB3 825T allele is predictive of enhanced Gi protein activation. This study was performed to correlate genotypes of the C825T polymorphism with various clinical aspects of chronic lymphocytic leukaemia (B-CLL). The GNB3 genotype distribution in B-CLL patients was similar to that in other Caucasian populations, arguing against a role of the polymorphism in the susceptibility to develop B-CLL. No statistically significant differences were observed at diagnosis between patients with the CC genotype and homozygous or heterozygous T allele carriers with respect to age at disease onset, sex distribution, proportion of patients with CD38+ leukaemia or patients in Binet stage A, blood cell counts, degree of bone marrow infiltration or serum levels of lactate dehydrogenase, thymidine kinase or beta2-microglobulin. In a subgroup of 44 patients requiring chemotherapy, the median interval between diagnosis and first treatment and the response to treatment were similar in patients with CC or CT/TT genotypes. A statistically significant difference, however, was found in the proportion of patients relapsing and requiring second line chemotherapy (CC: 95%; CT/TT: 52%; p = 0.0043). The GNB3 genotype (p = 0.024) and age (p = 0.042) were identified as independent prognostic factors for a second therapy. Thus, the long-term success of the treatment appears to be correlated with the GNB3 genotype.