OBJECTIVES: Syphilis infection persists globally contributing to preventable and treatable morbidity and mortality. How extensive early syphilis disseminates is unknown. To better understand the relationship between early syphilis infection and inflammation over time, our study enrolled six individuals recently infected with syphilis for sequential positron emission tomography (PET) scans. METHODS: We evaluated a case series of six individuals with high syphilis titres (two secondary, two early latent and two latent, unknown duration, but with high titre) who received sequential PET scans to assess inflammation over time and its response to treatment. RESULTS: At time of PET scan, four of the six individuals were co-infected with HIV. One of the four was not on antiretroviral therapy and three of the four were not virally suppressed (viral load of >400 copies/mL). Baseline rapid plasma reagin (RPR) titres ranged from 1:64 to 1:256 (four of the six participants had prior non-reactive RPR results). Five of the six participants had mild to intense hypermetabolic PET scan activity consistent with cervical (n=5), axillary (n=4), inguinal (n=5) and retroperitoneal (n=1) adenopathy. Mild hypermetabolic activity in the thoracic aortic wall, suggesting aortitis, was present among the same five participants and resolved within 30 days for four of the five participants and 60 days for the other participant. However, widespread lymphadenopathy remained present in PET scans up to 3 months following treatment in two participants. We did not find any abnormal PET scan activity of the central nervous system. CONCLUSION: We found abnormal aortic wall PET scan activity suggesting aortitis to be common in a case series of patients with early syphilis. In research settings, PET scans may be a sensitive tool to monitor inflammation associated with syphilis.