The goal of this clinical trial is to learn if doxycycline taken as 200mg daily for 14 days is effective to treat early stage syphilis. This is different from how doxycycline is typically used for syphilis because the full doxycycline dose will be taken at the same time of day, rather than split up into a twice daily regimen. Lab data support that taking the medication as a single daily dose should be effective as treatment, but it has not been studied clinically. The main question this study aims to answer is:

Is doxycycline taken as a single daily dose of 200mg for 14 days an effective treatment for early syphilis based on a combined outcome of clinical improvement and blood test improvement?

Participants will:

1. Take doxycycline 200mg daily for 14 days
2. Submit oral and rectal swabs that test for syphilis bacteria every other day for 2 weeks, returned by mail
3. Complete 2 brief online surveys over the first 2 weeks
4. Return to the clinic for an interview and blood draw every 3 months for a maximum of 3 study visits, including the first visit

The investigators will compare the percentage of participants in the study who have response to treatment by 6 months to that of persons who have received standard (CDC-recommended) regimens. To do this, the investigators will calculate response percentage estimates following a shot of long-acting penicillin or 14 days of doxycycline 100mg twice daily from 60-person samples from the sexual health program's records.

This is an open-label prospective cohort of 15 participants diagnosed with early syphilis treated with doxycycline 200mg daily for 14 days. The outcome of interest is clinical improvement and fourfold decline in RPR by 6 months. This study will include rectal and oropharyngeal sampling with syphilis transcription-mediated amplification (TMA), every other day for the 14-day course, returned by mail. The investigators will obtain 6-month point estimates for cure following single-dose intramuscular benzathine penicillin G or 14 days of doxycycline 100mg twice daily in retrospective cohorts of 60 persons. The investigators will use binomial exact calculation with an alpha of 0.05, two-tailed, to create a point estimates of percent cure. The investigators will report TMA positivity descriptively.

Inclusion Criteria:

Clinical diagnosis of syphilis (primary or secondary) or laboratory-confirmed early latent syphilis. Specifically: This will include persons meeting any one of the following criteria:

1. Clinical diagnosis of primary syphilis (based on the presence of a chancre) and either a positive qualitative RPR in the absence of a prior positive RPR on their most recent serological test for syphilis or a positive darkfield microscope exam of material taken from a chancre, OR
2. Clinical diagnosis of secondary syphilis with a positive qualitative RPR in the absence of a prior positive RPR on their most recent serological test for syphilis, OR
3. A laboratory-confirmed diagnosis of early latent syphilis within one month (i.e. <31 days prior).

Exclusion Criteria:

1. age under 18
2. persons with evidence of neurosyphilis (including ocular and otic syphilis) or tertiary syphilis
3. persons who are unable to give informed consent
4. persons deemed by the study investigators to be unable to complete study follow-up visits
5. persons with an allergy to doxycycline
6. pregnant persons
7. persons with HIV who report that they are off antiretroviral medication or that they are not virologically suppressed
8. persons with other known forms of immunosuppression (e.g., persons taking systemic immunosuppressant drugs, persons with primary immunodeficiencies)
9. persons taking medications that would interact with doxycycline
10. persons whose initial RPR is lower than 1:4
11. persons currently prescribed doxy PEP
12. breastfeeding persons

Persons whose initial laboratory serological tests do not confirm the diagnosis of syphilis with an RPR of 1:4 or higher will be informed that they do not meet study criteria and advised to discontinue doxycycline 200mg once daily. Their subsequent treatment will be based on the judgement of non-research, clinical staff in the clinic and reflect shared decision making between clinical providers and their patient.