Clostridioides difficile infection (CDI) prevention is a top issue for hospitals. Probiotics have the capacity to obstruct CDI and colonization. The impact of the computerized clinical decision support (CCDS) tool for prescribing probiotics for primary prevention of CDI among adult hospitalized patients was investigated in a study. In May 2019, four hospitals integrated a CCDS technology into their electronic medical records to urge the prescription of a probiotic preparation at the time of antibiotic prescription in high-risk patients. The hospital-wide CDI incidence was evaluated using interrupted time series and segmented regression analysis for the year prior to and after CCDS installation. In addition, after correcting for potential confounders, multivariable logistic regression was performed to assess CDI incidence in patients who qualified for probiotics in the pre-and post-intervention periods. Propensity score-matched pairs were created to evaluate CDI risk by receipt of probiotics to account for any variations in patients who received probiotics in the post-intervention period. Post-intervention, quarterly CDI incidence increased in comparison to baseline trends (slope change, 1.4; 95% confidence interval [CI],.9–1.9). For ineligible patients, the odds ratio (OR) of CDI was 1.41 post-intervention compared to pre-intervention (adjusted OR, 1.41; 95% CI, 1.11–1.79). Patients who received probiotics did not have lower incidences of CDI than those who did not (OR, 1.46; 95% CI,.87–2.45), according to a propensity score-matched study. Probiotics are not recommended for the main prophylaxis of CDI in adult inpatients receiving antibiotics.