Jarisch-Herxheimer reaction (JHR) is a transient clinical phenomenon in patients with syphilis who receive antibiotic treatment. A 31-year-old man with an underlying HIV infection presented with worsening vision in the right eye two days after being treated with oral doxycycline for presumed left-eye neuroretinitis. Prior history revealed two episodes of penile discharge and ulcers that were not investigated. Examination showed bilateral optic disc swelling with right eye placoid chorioretinitis around the macula. Optical coherence tomography (OCT) demonstrated right macular edema and left macular thinning. Blood investigations confirmed syphilis infection. Subsequently, the patient was scheduled for a contrasted brain CT with oral steroid coverage due to underlying allergies. His vision incidentally improved soon after the short course of steroids. Repeated OCT demonstrated marked improvement of right macular edema, which we believe was secondary to JHR initiated by the earlier doxycycline treatment. Following oral steroid addition, improvement in vision and ocular findings were seen. At six-month post-treatment, there was right macular atrophy as a sequela of the macular edema. Ophthalmologists should be aware of ocular-related JHR complications, particularly in potentiating macular atrophy following macular edema upon initiating antibiotic treatment in syphilitic disease.