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Prophylactic penicillin is effective in preventing severe invasive pneumococcal infection in children with sickle cell disease. In some families, compliance has been problematic. The aims of this study were to monitor compliance and to assess the efficacy of the Health Belief Model (HBM) in predicting compliance.Fifty mothers of children with sickle cell disease, ages 6 to 60 months, participated in the study. On enrollment, mothers completed surveys assessing their health beliefs regarding sickle cell disease and infections. Compliance was assessed through self-reporting by the mothers and through review of local pharmacy records of penicillin refills.Sixty percent of the mothers reported that they were highly compliant with obtaining the prescribed 14-day refills. Pharmacy records indicated that only 12% actually adhered to this schedule. The self-reports were significantly related to compliance ratings; mothers who admitted less than optimal compliance averaged 42 days between refills, compared with 19 days for mothers who reported good compliance. Varying perceptions identified through the HBM accounted for approximately 30% of the variance in compliance rates. The perceived burdens of picking up the refills and remembering to administer the medication were the most significant factors.Educational efforts alone are not sufficient to ensure compliance with penicillin prophylaxis. Routinely monitoring compliance through pharmacy records, reviewing parental beliefs about sickle cell disease and infections, and exploring barriers to treatment will promote dialogue about the importance of strict compliance with this relatively simple yet life-saving prophylaxis.