Chronic lymphocytic leukemia (CLL) is accompanied by increased risk of potentially fatal infections. While this can mostly be attributed to disease-related immune dysfunction, it is not known if CLL patients are also constitutionally susceptible to infections. We linked nation-wide Danish registers to explore this possibility, approximating infection susceptibility by use of antimicrobials. We assessed the incidence of antimicrobials among CLL patients and matched controls from the general population for up to 22 years before index diagnosis, and among children and grandchildren of CLL patients and their matched controls. Our analyses showed that for CLL patients overall antimicrobial use began to increase gradually six years before leukemia diagnosis. Before this time point, CLL patients had used significantly more macrolides (relative risk = 1.15; 95% confidence interval 1.10–1.20), antimycotics (1.18; 1.08–1.30), and antivirals (1.62; 1.45–1.81) than controls for up to 22 years before diagnosis. The same pattern of increased use was found among CLL patients’ children and grandchildren. Our study suggests that CLL diagnosis is preceded by decades of increased susceptibility to infections. The duration of this time window is compatible with causal roles of immune dysfunction and/or certain infections in CLL pathogenesis, possibly mediating the association between constitutional infection susceptibility and CLL risk.