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We describe a 39-year-old male who presented with a fever of unknown origin, the diagnostic work-up of which disclosed an acute cytomegalovirus (CMV) infection complicated by a partial superior mesenteric vein (SMV) thrombosis. Further investigations revealed the presence of factor V Leiden mutation. Oral anticoagulant treatment with warfarin led to a complete recanalization of SMV two months after. A literature review on the association between CMV infection and portal system (PS) thrombosis in immunocompetent patients was performed. We found that, in agreement with our case, in a minority of case reports patients did not complain of abdominal pain, but presented with a mononucleosis-like syndrome with malaise and prolonged fever and displayed a variable elevation of aminotransferase levels. Interestingly, most of them exhibited a limited extension of portal thrombosis. On the whole, these data suggest that PS thrombosis during acute CMV infection may be an underestimated complication.