Background: Late-onset ventilator-associated pneumonia (LVAP) is a major healthcare-associated infection contributing to significant morbidity, mortality, and healthcare costs in intensive care units (ICUs). LVAP, occurring 96 hours or more after intubation, is frequently associated with multidrug-resistant (MDR) pathogens. This study aimed to identify the determinants of LVAP, the microbial profile, and the impact on clinical outcomes among mechanically ventilated patients in a tertiary care hospital.Material and Methods: A 1:1 matched case-control study was conducted over 12 months in the ICU of SukhSagar Medical College, Jabalpur. A total of 280 patients (140 cases with LVAP and 140 controls without LVAP) were included. Cases were defined as patients who developed pneumonia 96 hours or more after intubation. Controls were matched based on APACHE II score and duration of mechanical ventilation. Data on demographics, clinical history, risk factors, microbiological findings, and outcomes were collected and analyzed using appropriate statistical tests.Results: Key risk factors for LVAP included prior use of steroids/immunosuppressants (18.6% vs. 2.1%; p = 0.003), re-intubation (16.4% vs. 3.6%; p = 0.018), and bacteremia (27.1% vs. 5.0%; p = 0.001). Patients with LVAP had a longer median duration of mechanical ventilation (16.5 vs. 11.0 days; p< 0.001) and ICU stay (21.0 vs. 16.0 days; p = 0.046). Mortality was significantly higher in LVAP cases (27.1% vs. 14.3%; p = 0.022). The most common pathogens were Acinetobacter spp. (49.3%) and Pseudomonas spp. (41.4%), with 59.3% of cases involving MDR organisms.Conclusions: LVAP is associated with significant risk factors, predominantly MDR Gram-negative bacteria, and worse clinical outcomes. Effective preventive strategies, early diagnosis, and targeted antibiotic therapy are critical to improving patient outcomes and reducing the burden of LVAP in ICUs.