To estimate the incidence of infection after diagnostic and operative hysteroscopic procedures performed in an in-office setting with different distension media (saline solution or CO2). Prospective, multicenter, observational study (Canadian Task Force classification II-2). Tertiary women's health centers. A total of 42,934 women who underwent hysteroscopy between 2015 and 2017. Of the 42,934 patients evaluated, 34,248 underwent a diagnostic intervention and 8686 underwent an operative intervention; 17,973 procedures used CO2 and 24,961 used saline solution as a distension medium. Patients were contacted after the procedure to record postprocedure symptoms suggestive of infection, including 2 or more of the following signs occurring within the 3 weeks after hysteroscopy: fever; lower abdominal pain; uterine, adnexal, or cervical motion tenderness; purulent leukorrhea; vaginal discharge or itchiness; and dysuria. Vaginal culture, clinical evaluation, transvaginal ultrasound, and histological evaluation were completed to evaluate symptoms. Operative hysteroscopies comprised polypectomies (n = 7125; 82.0%), metroplasty (n = 731; 15.0%), myomectomy (n = 378; 7.8%), and tubal sterilization (n = 194; 4.0%). Twenty-five of the 42,934 patients (0.06%) exhibited symptoms of infection, including 24 patients (96%) with fever, 11 (45.8%) with fever as a single symptom, 7 (29.2%) with fever with pelvic pain, and 10 (41.7%) with fever with dysuria. In 5 patients with fever and pelvic pain, clinical examination and transvaginal ultrasound revealed monolateral or bilateral tubo-ovarian abscess. In these patients, histological examination from surgical specimens revealed the presence of endometriotic lesions. The present study suggests that routine antibiotic prophylaxis is not necessary before hysteroscopy because the prevalence of infections following in-office hysteroscopy is low (0.06%).