CLL is the most prevalent form of adult leukemia. The life expectancy of patients affected by CLL varies significantly, with a large fraction of patients with survival expectation of 10 years or longer. Furthermore a number of patients are observed without treatment intervention. These patients have been labeled as “asymptomatic” and very little attention has been placed to the symptom burden that accompanies CLL. In order to measure the quality of life of patients with CLL, we explored the reliability and validity of the M. D. Anderson Symptom Inventory (MDASI). We enrolled 99 consecutive patients followed at our outpatient center. To assess and construct validity, we performed principal axis factor analysis with oblimin rotation. To assess reliability, we calculated separate coefficient alphas for the severity and interference subscale items. Patients were 63% male with a mean age of 59 years (range 29–79), with 43% age 60 years or older. 94% were White Non-Hispanic patients. 61% were employed. 83% had higher than high school education. 75% had Rai staging 0–1, and 53% had received prior treatment. Factor analysis of the MDASI items resulted in a two-factor solution (symptom severity and interferences) that satisfied criteria for interpretability and model fit in a confirmatory setting. Cronbach coefficient alphas for the MDASI were 0.91 for severity and 0.96 for interference. We also examined the criterion validity of the two MDASI subscales by investigating their correlation to similar subscales of the SF-12. MDASI “worst pain” was highly correlated with the “body pain” subscale of the SF-12 (r=−.84, p=.000). MDASI “fatigue” was significantly correlated with the SF-12 “energy” item (r=.79, p=.000). The patient self reported most severe symptoms were fatigue, sleeping disturbance, drowsiness, distress, and shortness of breath. There were no significant differences of symptom severity by age group (more or less than 60 years old) and by staging (Rai 0–1, 2–3). However, fatigue severity was significantly higher in patients who had more than 2 therapies than patients without prior therapy (4.26 vs 2.07 on 0 to 10 fatigue scale on MDASI, P=.003). The most burdensome symptoms were interference of working, activity and enjoyment of life. Moderate to severe symptoms that would be the targeted area of symptom control in CLL patients were fatigue (25%), drowsness, (13%), shortness of breath (11%), and sleeping disturbance (12%). In conclusion this preliminary data analysis showed that the MDASI is a reliable and valid tool for assessing symptom severity and interference with daily functioning in CLL patients. This versatile assessment tool can be used to measure CLL-related symptom burden in the clinical practice of symptom management as well as to measure changes in symptom burden in patients enrolled in therapeutic clinical trials.