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Patients with sickle cell disease are at increased risk of invasive infection despite gains made through penicillin prophylaxis, pneumococcal immunization and newborn screening. We present the case of a 42-year old male with hemoglobin SS disease, who developed acute multi-organ failure (MOF) secondary to Streptococcus pyogenes. He presented to the emergency department complaining of fever three times in five days, although a febrile at each presentation. On his third visit he became hemodynamically unstable and encephalopathic requiring intubation and admission to the ICU. His course was complicated by cardiomyopathy, acute renal insufficiency and bilateral trans metatarsal amputations. He was successfully discharged home on hospital day #37. We report on our experience with MOF from unrecognized infection in an adult with SCD, fever and review evidence-based and consensus treatment practices for management of sickle disease and fever in the emergency department. In conclusion, we strongly recommend that all fever in adults with sickle cell disease be treated as a medical emergency and receive empiric antibiotic therapy in addition to routine work-up and investigations.