A 27-year-old man with documented hypersensitivity to penicillin was treated intramuscularly for asymptomatic neurosyphilis with ceftriaxone (1 g daily for 14 days). After treatment the serum titer in the VDRL (Venereal Disease Research Laboratory) test declined from 32 to four dilutions. Lumbar punctures at months 3,6,9, and 28 after treatment revealed normalization of the cell count in cerebrospinal fluid and a decline in the VDRL titer in cerebrospinal fluid from four to one dilution(s). Western blot analysis revealed the presence in serum of IgG antibodies to at least 17 treponemal antigens and in cerebrospinal fluid of antibodies to at least ten treponemal antigens. Following ceftriaxone therapy serum and cerebrospinal fluid IgG reactivity to all antigens steadily decreased in intensity. These results indicate that ceftriaxone may provide a useful alternative therapy for penicillin-allergic patients with neurosyphilis. © 1986 American Sexually Transmitted Diseases Association.