Urethritis is a common condition predominantly caused by sexually transmitted pathogens such as Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium. It is not possible to differentiate with certainty between pathogens on the basis of clinical characteristics alone. However, empirical antibiotic therapy is often initiated in clinical practice. The aim of this clinical practice guideline is to promote an evidence-based syndrome-orientated approach to the management of male adolescents and adults with symptoms of urethritis. Besides recommendations for the diagnosis, classification and choice of treatment, this guideline provides recommendations for the indication to empirically treat patients with penile urethritis. A novel feature compared to existing, pathogen-specific guidelines is the inclusion of a flowchart for the syndrome-orientated practical management. For suspected gonococcal urethritis requiring empirical treatment, ceftriaxone is recommended. Due to the risk of Chlamydia trachomatis co-infection, doxycycline should also be prescribed, unless follow-up for the treatment of possible co-infections is assured. For suspected non-gonococcal urethritis, doxycycline is the recommended empirical treatment. In the empiric treatment of both gonococcal and non-gonococcal penile urethritis, azithromycin is reserved for cases where doxycycline is contraindicated. This guideline also includes detailed recommendations on differential diagnosis, pathogen-specific treatments and specific situations, as well as patient counselling and follow-up.