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Background Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by Chlamydia trachomatis (CT) serovars L1, L2, and L3 and is endemic among men who have sex with men (MSM) in Europe. We evaluated weekly oral azithromycin 1 g for 3 weeks as a treatment for LGV proctitis. Methods This is an open clinical trial with convenience allocation according to treating physician preferences. Adults with clinical proctitis received a single dose of 1 g of intramuscular ceftriaxone and were subsequently allocated to receive (i) doxycycline 100 mg twice daily for 21 days (Doxycycline group) or (ii) azithromycin 1 g orally once weekly for 3 weeks (Azithromycin group). LGV cure (primary endpoint) was defined as resolution of symptoms at week 6 (clinical cure, LGV-CC), with an additional supporting negative rectal polymerase chain reaction (PCR) at week 4 (microbiological cure, LGV-MC), if available. Results One hundred and twenty-five individuals with LGV clinical proctitis were included. All were MSM, and 96% were living with human immunodeficiency virus (HIV). Eighty-two were in the Azithromycin group, and 43 were in the Doxycycline group. LGV cure on a modified intention-to-treat analysis (primary endpoint), occurred in 80 of 82 (98%) in the Azithromycin group versus 41 of 43 (95%) in the Doxycycline group (treatment difference [95% confidence interval {CI}] 2.2% [−3.2, 13.2]). LGV-MC occurred in 70 of 72 (97%) vs 15 of 15 (100%) in the Azithromycin group and Doxycycline group, respectively (treatment difference [95% CI] −2.8% [−9.6; 17.7]). Adverse events were similar in both treatment groups. Conclusions Our findings support extended azithromycin dosing as an alternative treatment option for symptomatic LGV proctitis and provides the rationale for future randomized trials. [ABSTRACT FROM AUTHOR]