Objective: The aim of this prospective study was to assess the efficacy of antibiotic therapy for the prevention of adverse pregnancy outcomes in women with the amniotic fluid “sludge” at 15–24 weeks of gestation. Methods: 245 women underwent transvaginal ultrasound cervical length measurement at 15–24 weeks of pregnancy and 29 out of them with amniotic fluid “sludge” were included in the study. Eight women with the “sludge” had cervical length >25 mm (Group I), seven—an asymptomatic short cervix (Group IIa) and 14 women with a short cervix had symptoms like low abdominal pain, back pain, and menstrual-like cramps (Group IIb). All participants received intravenous, oral and/or vaginal antibiotic therapy. Participants in Group IIa were additionally given vaginal progesterone (VP), and in Group IIb—VP and indomethacin. Placentas from women with preterm birth (PTB) underwent histological examination. Results: The amniotic fluid “sludge” detected at an ultrasound scan between 15–24 weeks of gestation was associated with long-term maternal infections, histological chorioamnionitis, and was viewed as a marker of intra-amniotic infection. Absence of intravenous antibiotic therapy during midtrimester of pregnancy in these women was associated with neonatal infection with intrauterine onset in 61.1%, postpartum endometritis in 23.1%, and rate of PTB 46.2%. Intravenous antibiotic therapy eliminated sonographic presence of the sludge and resulted in prevented of neonatal and postpartum infections, prevented the risk of PTB in women with the cervical length >25 mm, in those with an asymptomatic short cervix receiving VP, and in 70% of symptomatic women with a short cervix, who received them in combination VP/indomethacin. For those women whose approach was not fully beneficial, it allowed to delay delivery in 11–17 weeks. Conclusions: Although we found that intravenous antibiotic therapy at 15–24 weeks of gestation in women with amniotic fluid “sludge” can protect from infection-related complications and demonstrated high beneficial effects of adding antibiotics to anti-inflammatory drug (indomethacin) and/or VP in women with a short cervix, further larger studies are needed. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.