Although penicillin remains highly effective in syphilis, important questions exist regarding the optimal regimen for syphilitic involvement of the nervous system. Progression of neurosyphilis despite 7.2 million units of penicillin G benzathine occurred in the case reported here, with subsequent resolution following high-dose intravenous aqueous penicillin therapy. This and other recent reports support the conclusion that neurosyphilis should be treated with higher amounts of penicillin than is provided by the benzathine regimens.