Background: MDRO colonization at ICU admission may identify patients at increased risk for hospital-acquired infection (HAI), but its independent predictive value remains incompletely defined. Methods: We conducted a retrospective observational study of 560 consecutive ICU admissions (July–October 2024). Admission screening assessed colonization with extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), and vancomycin-resistant enterococci (VRE). The primary outcome was microbiologically confirmed HAI; the secondary outcome was in-hospital mortality. Associations were evaluated using multivariable logistic regression, ROC/AUC analysis, mediation analysis, and a sensitivity analysis restricted to first admissions. Results: Of 560 admissions, 223 were screen-positive and 283 screen-negative. HAI occurred in 49 patients (8.8%). Positive screening was associated with increased HAI odds, narrowly missing significance in the primary adjusted analysis (OR 1.81, 95% CI 0.96–3.41, p = 0.065) but reaching significance in the first-admission sensitivity analysis (OR 2.09, p = 0.034). CRE showed the strongest adjusted association with HAI (OR 2.33, 95% CI 1.21–4.51, p = 0.012). Screening alone showed poor discrimination (AUC 0.574); combined with clinical variables, discrimination improved substantially (AUC 0.788). Conclusions: MDRO admission screening was associated with increased HAI odds, particularly for CRE, though screening alone has limited predictive performance. Larger prospective studies are needed to confirm these findings.