Does the “Obesity Paradox” Have an Expiration Date? A Retrospective Cohort Study

(1) Background: The “obesity paradox” refers to a protective effect of higher body mass index (BMI) on mortality in acute infectious disease patients. However, the long-term impact of this paradox remains uncertain. (2) Methods: A retrospective study of patients diagnosed with community-acquired acute infectious diseases at Shamir Medical Center, Israel (2010–2020) was conducted. Patients were grouped by BMI: underweight, normal weight, overweight, and obesity classes I–III. Short- and long-term mortality rates were compared across these groups. (3) Results: Of the 25,226 patients, diverse demographics and comorbidities were observed across BMI categories. Short-term (90-day) and long-term (one-year) mortality rates were notably higher in underweight and normal-weight groups compared to others. Specifically, 90-day mortality was 22% and 13.2% for underweight and normal weight respectively, versus 7–9% for others (p < 0.001). Multivariate time series analysis revealed underweight individuals had a significantly higher 5-year mortality risk (HR 1.41 (95% CI 1.27–1.58, p < 0.001)), while overweight and obese categories had a reduced risk (overweight—HR 0.76 (95% CI 0.72–0.80, p < 0.001), obesity class I—HR 0.71 (95% CI 0.66–0.76, p < 0.001), obesity class II—HR 0.77 (95% CI 0.70–0.85, p < 0.001), and obesity class III—HR 0.79 (95% CI 0.67–0.92, p = 0.003)). (4) Conclusions: In this comprehensive study, obesity was independently associated with decreased short- and long-term mortality. These unexpected results prompt further exploration of this counterintuitive phenomenon.