To explore whether prescription of evidence-based drug therapy is associated with better quality of life (QoL) in patients with heart failure (HF). Patients (n = 62) were recruited in the outpatient clinic of Groningen University Hospital. Inclusion criteria were previous diagnosis of HF, age 40-80 years; ejection fraction of less than 45%, free from other serious disease (such as cancer) and psychiatric problems in the last year. QoL was assessed with the RAND 36-item health survey questionnaire, on five scales: physical functioning, mental health, social functioning, vitality and general health perception. Medication prescribed for 1 to 6 months before the QoL assessment was classified as either evidence-based treatment or under-treatment, according to the 2001 European guidelines on optimal HF treatment. The study had a cross-sectional design. QoL did not differ significantly between evidence-based and under-treated patients, unadjusted or after adjustment for significant patient imbalances. Conventional step-up medication approach in HF may have a positive impact on survival or morbidity, but it seems not beneficial in relation to QoL. Other interventions should be designed to improve QoL of patients with HF.