The major histocompatibility complex is one of the interactive factors in the multifactorial model of carcinogenesis. Its main influence in experimental models is on the age at onset of malignancies. We have previously shown a similar effect of homozygosity for HLA-DR53 in CML. In the present study, we investigated 79 patients with CLL and 329 local controls from Germany. In addition to full serotyping, all patients and 116 of controls were also typed by HLA-DRB PCR analysis. The homozygosity rates for DR53 in patients under and over the median age (60 years) were 18.6% and 2.9%, respectively (p = 0.03). Eight of the 9 homozygous patients were under the median age. The sex ratio in the DR53 homozygous group was reversed in favour of females. The homozygosity rates for DR53 were different in the overall groups of patients and controls, yielding a relative risk (RR) of 2.4 (p = 0.03). This association was stronger in the early-onset group compared to age-matched controls (RR = 4.4; p = 0.008) and for females with an early onset compared to age- and sex-matched controls (RR = 17.9; p = 0.0008). The simultaneous occurrence of the alleles of the haplotype A2B62DR4 showed a strong association with CLL (RR = 4.1; p = 0.002). This was probably the reason behind the association with HLA-DRB1*0401 (RR = 2.4; p = 0.009). Compared to the accelerating effect of HLA-DR53, HLA-DR52 showed a significant delaying effect on the onset of CLL. These findings confirmed the influence of the HLA complex on the development of another leukaemia.