Persons living for long periods of time in malaria hyper-endemic areas may suffer from hyper-reactive malarial splenomegaly (HMS), a frequent cause of splenomegaly in such areas. Splenomegaly and sub-microscopic P. falciparum parasitaemia are hallmarks of HMS. Spleen has been suggested to play a protective antimalarial role and splenectomy may trigger symptomatic malaria attacks. Other causes of immune suppression may possibly reactivate latent malaria parasites. We report the case of an Italian 60-year-old male, who had spent 33 years in sub-Saharan Africa, who experienced a P. falciparum malaria attack 12 months after his return to Italy, concomitantly with a diagnosis of lung carcinoma possibly impairing his immune system.