To determine whether a new antibiotic regimen could reduce the frequency of intra-amniotic inflammation/infection in patients with preterm PROM.This retrospective cohort study was conducted to evaluate the effect of antibiotics on the frequency of intra-amniotic inflammation/infection based on the results of follow-up transabdominal amniocenteses from 89 patients diagnosed with preterm PROM who underwent serial amniocenteses. From 1993-2003, ampicillin and/or cephalosporins or a combination was used ("regimen 1"). A new regimen (ceftriaxone, clarithromycin and metronidazole) was used from 2003-2012 ("regimen 2"). Amniotic fluid was cultured and matrix metalloproteinase-8 (MMP-8) concentrations were measured.(1) The rates of intra-amniotic inflammation and intra-amniotic inflammation/infection in patients who received regimen 2 decreased during treatment from 68.8% to 52.1% and from 75% to 54.2%, respectively. In contrast, in patients who received regimen 1, the frequency of intra-amniotic inflammation and infection/inflammation increased during treatment (31.7% to 55% and 34.1% to 58.5%, respectively); and (2) intra-amniotic inflammation/infection was eradicated in 33.3% of patients who received regimen 2, but in none who received regimen 1.The administration of ceftriaxone, clarithromycin and metronidazole was associated with a more successful eradication of intra-amniotic inflammation/infection and prevented secondary intra-amniotic inflammation/infection more frequently than an antibiotic regimen which included ampicillin and/or cephalosporins in patients with preterm PROM.