To describe the epidemiology, clinical features, laboratory manifestations, response to therapy, and factors related to morbidity and mortality in a large group of patients with ehrlichiosis. Case-series. Laboratory-based surveillance in the United States. 237 patients whose serum had a fourfold increase or decrease in antibodies to Ehrlichia canis or E. chaffeensis. Epidemiologic, clinical, laboratory data, hospitalization, duration of illness, complications, and treatment response. From 1985 through 1990, 237 case-patients were identified in 21 states; rates exceeded 1 per 100 000 per year in only 5 counties. Incidence rates increased with age and were higher among men. Most case-patients had nonspecific illness and were not suspected of having a rickettsial infection. Many patients (60.8%) were hospitalized. Leukocyte and platelet counts typically decreased and liver function tests typically increased through day 7. Three (6.1%) of 49 outpatients treated only with tetracycline were hospitalized compared with 35 (92%) of 38 outpatients treated only with antibiotics other than tetracycline or chloramphenicol (P < 0.001). Among hospitalized patients, recovery was faster for those initially treated with tetracycline (median, 16 days) or chloramphenicol (median, 12 days) than for those initially treated with other antibiotics (median, 27 days; P = 0.03 for both comparisons). In a logistic regression analysis, severe illness or death was more probable among case-patients 60 years or older (odds ratio [OR], 4.60; 95% CI, 1.87 to 11.2) and among those who did not receive tetracycline or chloramphenicol until 8 or more days after symptom onset (OR, 4.38; CI, 1.36 to 14.0). The findings of this study are primarily representative of more seriously ill patients with human ehrlichiosis. Although rates are low, ehrlichiosis is found in many areas of the United States. Patients with a history of tick exposure, acute febrile illness, decreasing leukocyte counts, and decreasing platelet counts may have ehrlichiosis. Prompt treatment with tetracycline or chloramphenicol markedly decreases the morbidity.