Objective. To determine the factors leading to in-hospital mortality within 28 days in hospitalized patients with ARDS. It was a prospective observational cohort study conducted in Intensive Care Unit of Aga Khan University Hospital Karachi from March to August 2011. Methodology. Data was collected from patients admitted in the intensive care unit on the basis of inclusion and exclusion criteria. The patients were followed daily for 28 days to record any in-hospital complications and the outcome of patients. Results. Total of 46 patients were included during this period out of which 56% (26) were males and 43% (20) were females. Mean age was 44 ± 19 years. There were 11 (23.9%) patients with age >65 and 35 (76%) had age <65 years. There were 21 (45.6%) patients with pulmonary ARDS and 25 (54.3%) had extrapulmonary ARDS. APACHE II score of >20 was present in 23 (50%) patients while the rest had score of <20. Regarding in-hospital complications, 23 (50%) patients developed sepsis, 31 (67.4%) had multiorgan failure, 14 (30%) had refractory shock, and 15 (32.6%) developed refractory hypoxemia. Out of 46 patients, 26 (56.5%) died within 28 days. On univariate analysis, high APACHE score, multiorgan failure, refractory shock, and refractory hypoxemia were main causes of death. Conclusion. ARDS is a syndrome of high mortality with mortality rate of 56.5% in this study. High APACHE, sepsis, multiorgan failure, refractory shock, and refractory hypoxemia are the leading causes of death in our patients.