OBJECTIVES:  The European Society for Medical Oncology (ESMO) recommends treatment options in symptomatic, front-line CLL patients based on three subgroups: physically fit, the elderly/ those with major comorbidities, and del17p/TP53 mutated. Older, unfit, and del17p/TP53 mutated patients do not generally tolerate, or respond as well to, the full-dose fludarabine-based therapies used in physically fit patients. The primary objective of this study is to model the annual prevalence of symptomatic, treatment-naïve CLL patients considered unsuitable for treatment with full-dose fludarabine across the European Union (EU-28). METHODS:  A targeted literature search was conducted in Medline, Embase and other European onco-epidemiological sources. Model parameters were obtained through weighted mean values of incidence, prevalence, asymptomatic/symptomatic split, age, fitness and presence of del17p/TP53 abnormality. The following definitions were applied: eligible for front-line therapy (newly-diagnosed symptomatic CLL patients and those that transitioned from asymptomatic to symptomatic); elderly (patients aged 70 or older), and younger with comorbidity (those between 65 and 69 with a severe comorbidity). RESULTS:  Crude incidence rates varied across Europe (range 3.6/100,000-6.9/100,000) producing a weighted mean of 4.88 per 100,000. Model parameters of the proportion of treatment naïve patients with asymptomatic disease and the annual transition rate were 73.9% and 7.1% respectively. Applying these to the 2015 EU-28 population of approximately 508,243,000, the estimated number of patients eligible for front-line treatment was 15,545 (range 11,468–21,980). Utilizing weighted mean values of CLL age distributions, the proportion newly-diagnosed with major comorbidities and the proportion with del17p mutations, the number unsuitable for full-dose fludarabine-based therapies is estimated at 10,484 (range 7,735-14,825). Of these, 1,119 (range 826–1,583) are del17p/TP53 mutated and 9,365 (range 6,909–13,242) are considered elderly/younger with a severe comorbidity. CONCLUSIONS:  This study estimates the number of treatment-naïve CLL patients unsuitable for full-dose fludarabine-based therapies, who could potentially benefit from newer, more tolerable therapies.