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Objectives: To compare the incidence of healthcare-associated infections (HAI) and their outcomes between patients admitted to the ICU with sepsis and those admitted with non-sepsis diagnoses. Materials and methods: We performed a single-center, prospective, observational study of ICU patients at a tertiary level medical-surgical unit from April 2018 to October 2018. All patients admitted to the ICU with a length of stay (LOS) > 48 hours were included. Baseline data including demographics, co-morbidities, and severity of illness scores were collected. Index occurrence of HAI in all these patients was noted and data regarding organ support and patient outcomes were recorded. The incidence, complications, ICU LOS, and 30-day mortality of HAI were compared between the patients admitted to ICU originally with sepsis and non-sepsis diagnoses. Results: A total of 271 patients were evaluated in our study (N = 106 for the sepsis group and N = 165 for the non-sepsis group). No significant difference between the groups was found in the incidence of HAI (29.2% in sepsis group vs 24.4% in non-sepsis group; p = 0.07). Complications (acute kidney injury (AKI): 71 vs 45%; p = 0.01, shock: 81 vs 55%; p = 0.05, need for mechanical ventilation (MV): 30 vs 15%; p = 0.04) were more common in sepsis group compared to the non-sepsis group. The ICU LOS (12.2 ± 5.2 days vs 8.8 ± 2.05 days; p = 0.01) was significantly longer in the sepsis group. There was no significant difference in 30-day mortality between the groups (45 vs 25%; p = 0.07). Conclusions: The incidence of HAI seems to be similar between patients admitted with sepsis and non-sepsis diagnoses. However, patients admitted with sepsis develop higher rates of organ failure secondary to HAI and have a longer ICU LOS compared to patients admitted with non-sepsis diagnoses. The mortality rate of HAI did not differ between these two groups. [ABSTRACT FROM AUTHOR]