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Background: Plasmodium falciparum accounts for nearly all severe malaria cases among European travellers, even though, in areas of endemicity, Plasmodium vivax seems to cause severe malaria to a degree which is comparable with P. falciparum. Furthermore, unlike countries at high risk, the incidence of mixed infections among imported cases is very low. We report the case of a man from non-endemic country with a mixed infection diagnosed after a two-year stay in Guinea. Case Presentation: A 43-year-old male Italian patient developed hyperpyrexia and chills the day after his return to Italy. Within 7 days from fever onset, he was found unresponsive with vomiting and seizures. On admission to Emergency Room, the patient was hypotonic with flaccid tetraparesis, with a GCS score of 7. On the basis of personal and working history and clinical features, after exclusion of viral encephalitis, acute pyogenic meningitis, tubercular meningitis and pontine infarct, cerebral malaria infection was suspected. Rapid diagnostic test and peripheral blood smear were positive for plasmodium mixed infection (P. falciparum, P. vivax, Plasmodium ovale). Over the first 30 hours from admission, thrombocyte count dropped, and the patient developed disseminated intravascular coagulation. Renal failure required renal replacement therapy. Death occurred after 48 hours of ICU admission. Conclusion: The fatal course of the severe malaria with related cerebral impairment, lung and kidney failure, disseminated intravascular coagulation, severe acidosis, circulatory collapse with refractory septic shock and subsequent multi organ failure was likely due to delayed medical presentation by the patient and the mixed plasmodium infection. Diagnosis could only be established nine days after onset of symptoms.