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Objectives: Doxycycline is commonly prescribed as the primary prophylactic treatment for women undergoing hysterosalpingography (HSG). This study aimed to compare the prophylactic effectiveness and safety of azithromycin and doxycycline in terms of treating infections caused by HSG. Materials and Methods: This double-blind randomized clinical trial enrolled 107 women referred to Amiralmomenin Hospital in Arak, Iran, for HSG. After evaluation based on inclusion and exclusion criteria, the participants were randomly allocated to either the doxycycline or azithromycin group. The primary outcome was the incidence of adverse effects. The patients were also followed up to determine PCR test results for the clearance of chlamydia infection. Results: The cumulative incidence of side effects was 1.85% in the doxycycline group, with adverse effects observed in only one patient. Conversely, no adverse effects were reported in the azithromycin group (P = 0.505). In the doxycycline group, one patient (1.85%) tested positive in the PCR test, while no positive PCR tests were recorded in the azithromycin group. Neither group exhibited cases of fever or required additional treatments. The results of statistical analyses did not reveal any statistically significant differences between the compared groups (P > 0.05). Conclusions: A single dose of azithromycin could be considered interchangeable with a 1-week course of doxycycline as antibiotic prophylaxis in women undergoing HSG, as it provides similar effectiveness and safety.