Importance: The United States is experiencing a public health crisis due to an exponential rise in syphilis incidence, which can cause multi-systemic manifestations, including ocular syphilis. The standard of care treatment for ocular syphilis, a neuro-syphilis equivalent, has been intravenous (IV) aqueous crystalline penicillin G 18-24 million units per day for 10-14 days, however, this is costly to both the healthcare system and patients. Objective: To assess the efficacy of oral doxycycline to treat ocular syphilis when compared to standard of care IV penicillin. Design: Retrospective cohort study. Setting: Los Angeles General Medical Center, a large, urban academic medical center caring for underserved patients. Participants: 32 patients with ocular syphilis. Interventions: Patients received either doxycycline 200mg twice daily for 28 days as an outpatient or IV penicillin for 10-14 days through shared decision making. Main Outcomes: The main outcome measure was clinical resolution of ocular inflammation. Secondary outcome measures included visual acuity and serologic resolution (four-fold decrease in RPR titers). Results: Sixteen patients received oral doxycycline and sixteen patients received IV penicillin. There were no differences in age, sex, race, HIV infection, CD4 count, or treponemal test positivity between the cohorts. There was no difference in the rates of ocular inflammation resolution among patients who were treated with doxycycline or penicillin (p=0.62). Median visual acuity was better among patients receiving oral doxycycline than IV penicillin at presentation and final follow-up. Visual acuity change between presentation and final visit were similar between groups. Among patients with 9 months of follow-up, 4 out of 4 patients receiving doxycycline and 7/7 patients received IV penicillin achieved a four-fold crease in RPR titers. Conclusions: Oral doxycycline for the treatment of ocular syphilis may be safe and effective in a carefully selected subset of patients. An outpatient oral regimen has many benefits, most crucially in its avoidance of inpatient admissions, which are costly to the healthcare system and hazardous to the patient. Further prospective studies are required to evaluate the clinical and serologic effects of treating ocular syphilis with oral doxycycline.