BACKGROUND:Anaerobic organisms are important pathogens in acute pelvic inflammatory disease (PID). The currently recommended PID regimen of a single dose of ceftriaxone and doxycycline for 14 days has limited anaerobic activity. The need for broader anaerobic coverage is unknown and concerns have been raised about metronidazole tolerability. METHODS:We conducted a randomized, double-blind placebo-controlled trial comparing ceftriaxone 250 mg IM single dose and doxycycline for 14 days, with or without 14 days of metronidazole in women with acute PID. The primary outcome was clinical improvement at 3 days following enrollment. Additional outcomes at 30 days following treatment were the presence of anaerobic organisms in the endometrium, clinical cure (absence of fever and reduction in tenderness), adherence and tolerability. RESULTS:We enrolled 233 women (116 to metronidazole and 117 to placebo). Clinical improvement at 3 days was similar between the two groups. At 30 days following treatment, anaerobic organisms were less frequently recovered from the endometrium in women treated with metronidazole than placebo (8% vs 21%, p<0.05) and cervical Mycoplasma genitalium was reduced (4% vs. 14%, p<0.05). Pelvic tenderness was also less common among women receiving metronidazole (9% vs 20%, p<0.01). Adverse events and adherence were similar in each treatment group. CONCLUSIONS:In women treated for acute PID, the addition of metronidazole to ceftriaxone and doxycycline was well tolerated and resulted in reduced endometrial anaerobes, decreased M. genitalium and reduced pelvic tenderness compared to ceftriaxone and doxycycline. Metronidazole should be routinely added to ceftriaxone and doxycycline for the treatment of women with acute PID.