Organ dysfunction is common in patients with major burns and associated with poor outcomes. The risk factors for early onset multiple organ dysfunction syndrome (MODS) in major burn patients with invasive ventilator support has rarely been evaluated before. In this study, major burn patients with invasive ventilator support from 499 victims suffered in a mass casualty color dust explosion were retrospectively enrolled. The development of early MODS that occurred within 5 days after burn injury was determined and the risk factors associated with early MODS were analyzed. A total of 88 patients from five medical centers were included. Their mean total body surface area (TBSA) was 60.9 ± 15.8%, and 45 (51.1%) patients had early MODS. Hematologic failure was the most common organ failure (68.6%), followed by respiratory failure (48.9%). Independent clinical factors associated with early MODS included TBSA ≥55% (OR: 3.83; 95% CI: 1.29-11.37) and serum albumin level <2.1 g/dL upon admission (OR: 3.43; 95% CI: 1.01-11.57). Patients with early MODS had prolonged ventilator dependence and longer ICU admission than those without early MODS. Our results showed that early MODS in major burn patients with invasive ventilator support is very common and can be predicted early on admission.