We report the case of a 20-year-old male complaining of sudden-onset, severe headaches, fever, chills, and generalized arthralgia. He had no symptoms of a respiratory tract infection. Blood examination revealed severe leukopenia and mild to moderate thrombocytopenia. Onset of symptoms was rapid, intense, and occurred only a few hours after routine tick-borne encephalitis (TBE) booster vaccine. The question of a relationship between booster vaccine administration and the febrile illness with bicytopenia was raised. A broad range of diagnostics excluded infections and other causes for bicytopenia. Symptoms resolved within a few days, and blood counts normalized within two weeks. Due to the close temporal relationship, a transient benign bicytopenia and febrile illness as a systemic reaction to TBE vaccination was assumed. Review of the literature and adverse event reporting systems suggest that this is a very rare reaction.