In the last 10 years, Belgium and countries of the European Economic Area and other high-income countries observed an increasing trend in syphilis diagnoses. Men who have sex with men (MSM) are the most affected population explained by high rates of unprotected sex, a greater number of sexual partners, and risk compensation as a result of pre-exposure prophylaxis use. The 2019 European Centre for Disease Prevention and Control (ECDC) technical report on syphilis proposed interventions such as enhanced screening of specific populations at risk. This guideline will address these issues. We performed a systematic review of the evidence for diagnosing and treating syphilis. Based on the results, recommendations were formulated for primary health care professionals in Belgium. This syphilis guideline addresses prioritised testing, the sample and test for the diagnosis, the treatment of a person with syphilis including syphilis serology follow-up, and partner management. The identification and management of patients with syphilis will benefit from the application of this guideline.