Background: Timely antibiotic de-escalation is essential in intensive care unit (ICU) to prevent the development of antibiotic resistance. This study was undertaken to identify the causes and observe the effects of late antibiotic de-escalation on mortality, length of stay, duration of mechanical ventilation, antibiotic-associated adverse effects, incidence of new infections, and growth of drug-resistant organisms in ICU. Methods: This retrospective study was conducted in a university hospital. A total of 76 consecutively admitted ICU patients were included after retrieving all information from the hospital database and obviating the need for IEC approval. All the enrolled patients had antibiotics initiated and de-escalated in ICU. Those patients for whom antibiotics were initiated before ICU admission were enrolled if their antibiotic prescription was unchanged on ICU admission. Patients with antibiotic de-escalation outside ICU were excluded. The two groups: N-antibiotic de-escalation <8 days and L-antibiotic de-escalation <8 days after ICU admission were compared with respect to all variables and analyzed using software R. Results: Of 76 patients, 41 (53.9%) were N and 35 (46.1%) were L. The mean antibiotic duration was 6 ± 1.5 versus 11 ± 3.4 days (N vs. L; P = 0.04). Prior antibiotic administration within 30 days was 6 versus 12 (N vs. L; P = 0.03). More incidences of “new infections” and drug-resistant organisms occurred in L (19.5% vs. 34.2%; P = 0.04 and 9.7% vs. 25.8%; P = 0.02, respectively). Prior antibiotic administration was independently associated with higher mortality risk in L (odds ratio - 2.34; confidence interval - 1.45-3.48; P = 0.01) and caused greater mortality in L (P = 0.03). Conclusions: Late antibiotic de-escalation in ICU was caused primarily due to persistence of infection and was associated with higher incidence of “new infections” and drug-resistant organisms and higher mortality in patients receiving antibiotics in the preceding 30 days.