We describe the case of a 3-year-old girl, admitted to the pediatric ward for three repeated episodes of severe migraine associated with vertigo, with onset 1 week after complete remission from an episode of chicken pox (i.e., varicella-zoster virus infection). All radiological and laboratory examinations were normal, except for a markedly elevated value of D-dimer (i.e. 8998 ng/ml; local reference range: < 243 ng/ml), measured with a commercial latex-enhanced immunoturbidimetric assay. After physical and Doppler ultrasound examination, possible presence of thrombosis was ruled out, and the patient was discharged. In the following year, however, her plasma D-dimer values always remained frankly elevated, so that an analytical interference was suspected. A plasma sample was treated with a specific heterophilic antibodies blocking reagent and then assayed along with the untreated sample, with these showing a marked discrepancy of D-dimer values, that is 232 versus 2877 ng/ml. These results, highly indicative for the presence of heterophilic antibodies, are discussed in the light of the serious challenges that this type of analytical interference may pose on quality and reliability of D-dimer testing.