Objective To demonstrate the infectious nature of chronic endometritis (CE) in an inductive way by comparing the results of germ-oriented antibiotic therapy vs. no treatment in women with CE. Design Retrospective, nonconcurrent case-control study. Setting Tertiary hysteroscopic center in a university teaching hospital. Patient(s) Sixty-four consecutive women with CE who received antibiotic therapy (Group A) compared with a historical group of 64 patients with CE who refused antibiotic therapy (Group B). Interventions(s) CE was diagnosed through hysteroscopy, histology, and immunohistochemistry for CD138. Patients in both groups were tested for CE twice to evaluate the cure rate after antibiotic therapy (Group A) or no treatment (Group B). For patients with persistent disease, antibiotic therapy was repeated up to 3 times. Antibiotics were chosen based on endometrial culture (with antibiogram). Main Outcome Measure(s) The primary outcome was to compare the cumulative cure rate of CE (defined as the percentage of patients without CE at the test of cure) between groups. Result(s) Among Group A, 20 patients (31.25%) experienced CE resolution after 1 antibiotic cycle, an additional 20 patients (31.25%) after 2 antibiotic cycles, and 12 patients (19.35%) after 3 antibiotic cycles. In 12 cases (18.75%), CE was persistent after 3 cycles of antibiotics. The cure rate of CE in Group A after 1 cycle of antibiotics was significantly higher than that of Group B (32.25% vs. 6%). Similarly, the cumulative cure rate was considerably higher in Group A vs. Group B (81.3% vs. 6%). Notably, the number of positive cases decreased significantly with all techniques between the first and second evaluation, whereas at the third evaluation, there was a statistical decrease only with hysteroscopy and CD138+ cell count but not with histology. The cumulative number of cases of CE diagnosed at hysteroscopy was significantly higher than histology and immunohistochemistry. Conclusion(s) Our study demonstrated the superiority of antibiotic therapy compared with no treatment for CE cure. Accordingly, the infectious nature of CE is inferred.