The efficacy of intravenous ceftriaxone, 2 g per day for 30 days, was evaluated in a case series of 18 consecutive patients who met strict criteria for Lyme encephalopathy. Months to years after classic manifestations of Lyme disease, the 18 patients presented with memory difficulty, minor depression, somnolence, or headache. Sixteen (89%) had abnormal memory scores; 16 (89%) had cerebrospinal fluid (CSF) abnormalities, and all 7 patients tested had frontotemporal perfusion defects on single photon emission computed tomographic (SPECT) imaging. Six months after treatment, memory scores in the 15 patients who completed the study according to protocol were significantly improved (P<.01). In the 10 patients who had follow-up CSF analyses, total protein levels were significantly lower (P<.05). In the 7 patients who had SPECT imaging, posttreatment perfusion was significantly better (P<.01). Twelve to 24 months after treatment, all 18 patients rated themselves as back to normal or improved. We conclude that Lyme encephalopathy can be treated successfully with ceftriaxone.