A randomized, multicenter, investigator-blinded clinical trial was undertaken in order to compare the efficacies of cefuroxime axetil and doxycycline in the treatment of patients with Lyme disease associated with erythema migrans. A total of 232 patients with physician-documented erythema migrans were treated orally for 20 days with either cefuroxime axetil, 500 mg twice daily (119 patients), or doxycycline, 100 mg three times daily (113 patients), and clinical evaluations were conducted during treatment (8 to 12 days) and at 1 to 5 days and 1, 3, 6, 9, and 12 months posttreatment. Patients were assessed as to the resolution of erythema migrans and of the signs and symptoms related to early Lyme disease as well as to the prevention of late Lyme disease. A satisfactory clinical outcome (success or improvement) was achieved in 90 of 100 (90%) evaluable patients treated with cefuroxime axetil and in 89 of 94 (95%) patients treated with doxycycline (difference, -5%; 95% confidence interval, -12 to 3%). Patients with paresthesia, arthralgia, or irritability at enrollment were at higher risk for an unsatisfactory clinical outcome at 1 month posttreatment. Of the patients with satisfactory outcomes at 1 month posttreatment who were evaluable at 1 year posttreatment, a satisfactory outcome was achieved in 62 of 65 (95%) and in 53 of 53 (100%) patients treated with cefuroxime axetil and doxycycline, respectively (difference, -5%; 95% confidence interval, -10 to 4%). Twenty-eight percent of patients treated with doxycycline and 17% of those treated with cefuroxime axetil had one or more drug-related adverse events (P = 0.041). Doxycycline was associated with more photosensitivity reactions (6% compared with 0% for patients treated with cefuroxime axetil; P=0.006), and cefuroxime axetil was associated with more cases of diarrhea (5% compared with 0% for patients treated with doxycycline; P=0.030). Jarisch-Herxheimer reactions occurred in 12% of the patients in each treatment group. In summary, cefuroxime axetil is well tolerated and appears to be equally as effective as doxycycline in the treatment of early Lyme disease and in preventing the subsequent development of late Lyme disease.