AbstractChronic lymphocytic leukemia (CLL) therapies differ in efficacy, side effects, route, frequency, and duration of administration. We assessed patient preferences for treatment attributes and evaluated associations with disease stage, treatment line, and socio‐demographic characteristics in a cross sectional, observational study conducted at 16 Italian hematology centers. Study visits occurred between February and July 2020; 401 adult patients with CLL (201 Watch and Wait (W&W), 200 treated) participated in a discrete choice experiment (DCE), composed of 8 choices between pairs of treatment profiles with different levels of 5 attributes of currently available CLL treatments (length of response, route and duration of administration, risk of side effects including diarrhea, infections, or organ damage). Health‐related quality of life was assessed with the EQ‐5D‐5L, EORTC QLQ‐C30 and QLQ CLL‐16. Previously treated patients had longer disease duration (7 vs. 5 years), higher prevalence of serious comorbidities (45.5% vs. 36.2%) and high‐risk molecular markers (unmutated IGHV 55.6% vs. 17.1%; TP53 mutation 15.2% vs. 4.0%). Health‐related quality of life scores were similar between groups. In the DCE, W&W patients rated “possible occurrence of infections” highest (relative importance [RI] = 36.2%), followed by “treatment and relevant duration” (RI = 28.0%) and “progression‐free survival (PFS)” (RI = 16.9%). Previously treated patients rated “treatment and relevant duration” highest (RI = 33.3%), followed by “possible occurrence of infections” (RI = 28.8%), “possible occurrence of organ damage” (RI = 19.4%), and “PFS” (RI = 9.8%). Concern over infection was rated highest overall; unexpectedly PFS was not among the most important criteria in either group, suggesting that the first COVID‐19 pandemic wave may have influenced patient preferences and concerns about CLL therapy options.