To compare the efficacy of oral doxycycline and IV penicillin G for the treatment of neuroborreliosis, we randomized consecutive patients with Lyme neuroborreliosis to receive either IV penicillin G (3 g q 6 h) or oral deoxycycline (200 mg q 24 h) for 14 days. All patients had antibodies against Borrelia burgdorferi in serum, CSF, or both, or had a positive CSF culture. Twenty-three patients randomized to penicillin G and 31 patients to doxycycline were included in the study. All patients improved during treatment, and there were no significant differences between the two treatment groups in patient scoring, CSF analysis, or serologic and clinical follow-up during 1 year. There were no treatment failures, although one patient in each treatment group was re-treated because of residual symptoms. In conclusion, oral doxycycline is an adequate and cost-effective alternative to IV penicillin for the treatment of Lyme neuroborreliosis.