Despite published reports regarding the association of elevated circulating CD44 and CD54 levels with unfavorable outcome in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), little is known about therapy-related changes in either adhesion molecule. In an attempt to evaluate the effect of interferon-alpha (IFNalpha), the authors measured serum CD44 (sCD44) and sCD54 in 22 low grade NHL and 14 CLL patients.Twenty-six patients fulfilling the criteria for therapy received daily doses of 3 x10(6) IU IFNalpha-2a. Ten patients not requiring therapy also were observed for the same period. Fasting sera were collected at baseline and in 4 monthly intervals from all patients including the IFNalpha-treated (Group 1) and the untreated group (Group 2).Higher baseline sCD44 values were observed in Group 1 as compared with the Group 2 patients (P = 0.057). Within Group 1, patients were further divided between those who responded to IFNalpha, referred to as responders, and those who did not respond to IFNalpha, known as nonresponders. Responders showed a gradual decrease in sCD44 starting at the 4th month until the 12th month (P = 0.003, P = 0.002, and P = 0.01). Neither a difference in baseline nor an IFNalpha effect on the sCD54 levels could be shown. Soluble CD44 levels between responders and nonresponders were not different at the baseline but were significantly lower in responders, starting at month 4 and continuing throughout the therapy period (P = 0.04, P = 0.017, and P = 0.043). This decrease did not accompany a leukocyte or lactate dehydrogenase decrease and was not correlated with an early disappearance of the clinical findings. Similarly, after treatment, the sCD44 values of Group 1 were lower than the Group 2 levels at months 4 and 8 (P = 0.007 and P = 0.05, respectively).Soluble CD44, but not sCD54, can be used for monitoring therapy in patients with low grade NHL and CLL who have received IFNalpha, and for deciding whether further IFN therapy is necessary for those patients who have not responded to IFNalpha over a previous 12-month period.