Background <p>Controlling the syphilis epidemic in Australia is a public health priority. Regular intramuscular (IM) injections of benzathine penicillin G (BPG) are the current standard of care for late latent syphilis in Australia; however, repeated IM BPG injections are painful, and treatment completion rates are low. Early-phase clinical trials have demonstrated the tolerability and safety of high-dose subcutaneous infusions of BPG (SCIP), where the total treatment dose can be delivered at a single visit. Here we describe the experiences and preferences of attendees of Western Australian sexual health clinics in the Perth metropolitan region who have syphilis and were treated with SCIP.</p> Methods <p>This was a mixed methods sub-study of a phase IIa clinical trial (ACTRN12622000349741). Eligible participants attended South Terrace Sexual Health Clinic in Fremantle, Western Australia, after referral from physicians to the South Metropolitan Health Service. Nine participants were followed up with for 24 weeks after receiving SCIP. Semi-structured interviews were conducted at three time points. All interviews were audio recorded, transcribed verbatim and underwent content and thematic analyses.</p> Results <p>Two themes were identified: (1) tolerance of SCIP and (2) SCIP is preferred over IM BPG. SCIP was well-tolerated by participants, who praised the ease and convenience of the procedure. Participants described instances of mild to moderate pain during and after SCIP, substantiated by self-reported pain scores and adapted Skindex-16 scores. All participants stated that they would prefer SCIP over IM BPG as syphilis treatment, and that they would be willing to receive SCIP again should re-infection occur.</p> Conclusion <p>All participants described tolerable infusion experiences with a clear preference for SCIP over IM BPG to treat syphilis. SCIP has potential to replace IM BPG in clinical practice. Further research is needed to determine the acceptability and efficacy of SCIP in diverse cohorts.</p>