Abstract Objectives To determine if the Charlson comorbidity index (CCI) is an accurate predictor of unplanned readmissions for patients using outpatient parenteral antimicrobial therapy (OPAT) services. Methods Retrospective analysis of patients >16 years of age who had received OPAT at Lancashire Teaching Hospitals between 2019 and 2021. The number of unplanned hospitalizations was measured and categorized as OPAT related or non-OPAT related. The CCI for each patient group was calculated using an online tool, and logistic regression was used to assess the association between risk factors and risk of being readmitted. Results The cohort consisted of 741 patients. Unplanned readmission was seen in 112 patients (15.1%). The mean CCI score for patients with OPAT-related readmissions was 4.22, 0.92 higher than the mean for patients who were not readmitted (3.30). The mean CCI score for patients with non-OPAT-related readmissions was higher still at 4.89. The logistic regression showed that increased CCI, age, male gender and home location compared with clinic were associated with increased odds of readmission, although these effects did not meet statistical significance. Conclusions These results suggest that a higher CCI score is associated with a non-statistically significant increased risk of unplanned hospitalization. We concluded that the CCI may therefore be used in future decision-making regarding the acceptance of patients to OPAT and requires further investigation.