Tick-borne rickettsiae in the genera Ehrlichia and Anaplasma are intracellular bacteria that infect wild and domestic mammals and, more recently, man. The increased desire of humans for recreational activities outdoors has increased the exposure to potential human pathogens that previously cycled almost exclusively within natural, nonhuman enzootic hosts. Anaplasma phagocytophilum causes an acute, nonspecific febrile illness of humans previously known as human granulocytotropic ehrlichiosis (HGE) and now called human granulocytotropic anaplasmosis (HGA). The first patient to have recognized HGA was hospitalized at St Mary's Hospital in Duluth, Minnesota, USA in 1990. However, the clinical and laboratory presentation of this infection remained undefined until 1994, when Bakken and collaborators published their experience with 12 patients who had HGA. By the end of December 2004, at least 2,871 cases of HGA had been reported from 13 U.S. states to the Centers for Disease Control and Prevention (CDC). A limited number of laboratory-confirmed cases have been reported from countries in Europe, including Austria, Italy, Latvia, the Netherlands, Norway, Poland, Slovenia, Spain, and Sweden. Ixodes persulcatus-complex ticks are the arthropod hosts for Borrelia burgdorferi, the agent of Lyme borreliosis, and are also the arthropod hosts for A. phagocytophilum. Most cases of HGA have been contracted in geographic regions that are endemic for Lyme borreliosis. Male patients outnumber female patients by a factor of 3 to 1 and as many as 75% of patients with HGA have had a tick bite prior to their illness. Seroepidemiologic studies have demonstrated that HGA for the most part is a mild or even asymptomatic illness. However, older individuals and patients who are immunocompromised by natural disease processes or medications may develop an acute, influenza-like illness characterized by high fever, rigors, generalized myalgias, and severe headache. Local skin reactions at the site of the tick bite have not been described, and nonspecific skin rashes have been reported only occasionally. Anaplasmosis is associated with variable but suggestive changes in routine laboratory test parameters. Most patients develop transient reductions in total leukocyte and platelet concentrations. Relative granulocytosis accompanied by a left shift and lymphopenia during the first week of illness has been reported frequently. Serum hepatic transaminase concentrations usually increase two- to fourfold, and inflammatory markers, such as C-reactive protein and the erythrocyte sedimentation rate, rise during the acute phase. Abnormal laboratory findings may return toward normal range for patients who have been ill for more than 7 days, which may obfuscate the clinical decision making. Characteristic clusters of bacteria (morulae) are observed in the cytoplasm of peripheral blood granulocytes in 20% to 80% of infected patients during the acute phase of illness. The clinical diagnosis may be confirmed retrospectively by specific laboratory tests, which include positive polymerase chain reaction (PCR), identification of A. phagocytophilum in culture of acute-phase blood, or the detection of specific antibodies to A. phagocytophilum in convalescent serum. Virtually all patients have developed serum antibodies to A. phagocytophilum after completion of antibiotic therapy, and demonstration of seroconversion by indirect immunofluorescent antibody testing of acute-phase and convalescent-phase serum samples is currently the most sensitive and specific tool for laboratory confirmation of HGA. Treatment with doxycycline usually results in rapid improvement and cure. Most patients with HGA have made an uneventful recovery even without specific antibiotic therapy. However, delayed diagnosis in older and immunocompromised patients may place those individuals at risk for an adverse outcome, including death. Thus, prompt institution of antibiotic therapy is advocated for any patient who is suspected to have HGA and for all patients who have confirmed HGA.