Radiology referral quality impacts patient care, yet factors influencing quality are poorly understood. This study assessed the quality of computed tomography (CT) referrals, identified associated characteristics, and evaluated the ESR-iGuide clinical decision support tool’s ability to optimize referrals. A retrospective review analyzed 300 consecutive CT referrals from an acute care hospital. Referral quality was evaluated on a 5-point scale by three expert reviewers (inter-rater reliability κ = 0.763–0.97). The ESR-iGuide tool provided appropriateness scores and estimated radiation exposure levels for the actual referred exams and recommended exams. Scores were compared between actual and recommended exams. Associations between ESR-iGuide scores and referral characteristics, including the specialty of the ordering physician (surgical vs. non-surgical), were explored. Of the referrals, 67.1% were rated as appropriate. The most common exams were head and abdomen/pelvis CTs. The ESR-iGuide deemed 70% of the actual referrals “usually appropriate” and found that the recommended exams had lower estimated radiation exposure compared to the actual exams. Logistic regression analysis showed that non-surgical physicians were more likely to order inappropriate exams compared to surgical physicians. Over one-third of the referrals showed suboptimal quality in the unstructured system. The ESR-iGuide clinical decision support tool identified opportunities to optimize appropriateness and reduce radiation exposure. Implementation of such a tool warrants consideration to improve communication and maximize patient care quality.