The diagnosis and treatment of syphilis can present difficult dilemmas. Serologic tests can be negative if they are performed at the stage when lesions are present, and the VDRL test can be negative in patients with late syphilis. Cerebrospinal fluid examination is not required in patients with primary or secondary disease and no neurologic signs or symptoms, but it may be warranted in patients with late latent syphilis or in whom the duration of infection is unknown. Patients with penicillin allergy can be treated with alternative regimens if they have primary or secondary syphilis. Penicillin is the only effective drug for neurosyphilis; oral desensitization should be accomplished before treatment of penicillin-allergic patients. Other dilemmas may be encountered in the treatment of patients who have concurrent human immunodeficiency virus infection.