The evolution of treatment guidelines for early syphilis to single-dose benzathine penicillin regardless of HIV status has been controversial in the UK. We describe the treatment response in patients treated by current and previous regimens of benzathine penicillin for early syphilis. We found no difference in treatment efficacy between single-dose benzathine and previously recommended benzathine treatment courses in HIV co-infected patients. HIV-positive status did alter treatment efficacy as evidenced by increased serological cure rates at 12 months, although this was not statistically significant. This may be due to the loss to follow-up in HIV-negative patients. HIV-infected patients were increasingly likely to be re-infected with syphilis compared to HIV-negative patients. Our findings also justify the screening of HIV patients with syphilis serology at each routine HIV follow-up.