Analgesia and hydration remain the only safe treatment for painful crises of sickle cell disease; hydroxyurea is effective, but the toxicity is still a problem. Piracetam is a nootropic drug that has reportedly been effective and non-toxic in sickle cell patients, but most studies were not placebo-controlled and included a small number of patients. The present study evaluated the drug in a double-blind crossed placebo-controlled clinical trial in 73 children and adolescents suffering from moderate to severe painful crises for 13 months. Information regarding frequency and severity of pain was acquired through monthly clinical evaluation, visits and house calls, and 4,300 weekly questionnaires filled out by the patients in their domiciles. A monthly pain score was calculated for each patient. Pain was the most frequent adverse manifestation of the disease stressing its significant bio-psycho-social impact. Although nearly all patients and relatives reported a better clinical course throughout the whole study, the drug was ineffective in the prevention of painful crises. This placebo effect may be ascribed to an unplanned and unsystematic ‘cognitive-behavioural’ management of the children. The pain score in the second semester of the study – both in the experimental and in the control groups – was significantly smaller than that in the first semester. In conclusion, piracetam was found to be ineffective in the prevention of painful crises; a powerful placebo effect due to adequate patient care was demonstrated.