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Background/Objectives: Blood is often the first organ to show changes during local or systemic infection, but common definitions of sepsis rarely include CBC findings in risk assessment tools. Infection remains the main cause of sepsis, which Sepsis-3 defines as life-threatening organ dysfunction from a dysregulated immune response. Changes in circulating monocytes—such as altered MDW and increased inflammation—can be seen in sepsis and SARS-COV-2. This study evaluates MDW as a blood marker for detecting infections and compares it with traditional markers for risk stratification. Methods: From December 2021 to December 2023, 608 adults with suspected infection or sepsis were enrolled at San Donato Hospital's Emergency Department in Arezzo. All patients were admitted and monitored in assigned wards, with destination, history, clinical, and lab data collected during their stay and follow-up. Results: Monocyte Distribution Width (MDW) detects bloodstream infection with high efficacy (sensitivity 92%, specificity 85%, and negative predictive value 95% at ER admission). MDW also stratifies risk for infections that may progress to sepsis—including urinary, respiratory, post-surgical, and wound infections—with sensitivity, specificity, and negative predictive value around 70–72%. Conclusions: Blood is usually the first organ to show changes during infection, with blood cell morphology and CBC parameters affected by bacterial, viral, or fungal pathogens. Techniques like flow cytometry and impedance measurements provide Cell Population Data (CPD), such as MDW, which support diagnostic algorithms for infection or sepsis. CPDs are well-suited for AI analysis, and the extensive information from CBCs should be integrated into both diagnosis and treatment.