OBJECTIVES: As outcomes research is being used to inform the decision-maker about continuation of reimbursement of expensive hospital drugs in the Netherlands since 2006, this type of research is becoming more important. Our study started before 2006 and aimed to evaluate therapies in daily clinical practice and their costs and outcomes. This study gives an indication of the challenges that may arise from the design of outcomes research. METHODS: An observational follow-up study was performed including 160 patients with chronic lymphocytic leukemia (CLL). Data collection on treatment, costs and outcome was performed in 19 Dutch hospitals using medical records. RESULTS: Patients diagnosed between 1999 and 2003 were included and followed during 6.4 years on average. The mean age was 63 years (range: 30-86). 20% received one therapy-line, 12% two and 24% received three or more therapy-lines. Most patients received chlorambucil (87%) as first therapy and the second line was dominated by fludarabine (46%). However, therapies from the third line onwards varied extensively. Due to the development of new medicines like monoclonal antibodies, the treatment sequence changed in the more recently diagnosed patients. As a consequence of the relatively low incidence of CLL and the variety in therapy, the number of patients with comparable therapies was small. CONCLUSIONS: Management of CLL varied strongly especially after the second therapy-line. This may be caused by the introduction of monoclonal antibodies as first and second line treatment during the study period. Additionally, a comparison of alternative therapies was hampered due to relative small number of patients. Consequently, modeling studies or patient registrations might be necessary to obtain valid information about cost-effectiveness of new expensive inpatient medicines in (chronic) diseases with a low incidence rate and a highly variable or changing management strategy.