Purpose: To prospectively assess the incidence of delayed adverse reactions (DARs) in patients undergoing contrast material-enhanced computed tomography (CT) with the low osmolar nonionic contrast agent iohexol and compare with the incidence of DARs in patients undergoing unenhanced CT as control subjects. Materials and Methods: Institutional review board approval and informed written consent for this prospective study were obtained. The study was HIPAA compliant. Patients undergoing CT for routine indications were enrolled from a random next-available scheduling template by an on-site clinical trials monitor. All subjects received a questionnaire asking them to indicate any DAR occurring later than 1 hour after their examination. Sixteen manifestations were listed and included rash, skin redness, skin swelling, nausea, vomiting, and dizziness, among others. To ensure maximal surveillance, a clinical trials coordinator initiated direct telephone contact for further assessment. Patients suspected of having moderately severe cutaneous reactions were invited to return for a complete dermatologic clinical assessment including skin biopsy, if indicated. Statistical analysis was performed by using a twosided Wilcoxon-Mann-Whitney test, a logistic regression utilizing a x2 test to adjust for sex and age, and a two-sided Fisher exact test. Results: A total of 539 patients (258 receiving iohexol and 281 not receiving contrast material) were enrolled. DARs were observed in 37 (14.3%) of 258 subjects receiving iohexol and in seven (2.5%) of 281 subjects in the control group (P<.0001, x2 test) after adjusting for sex and age. Specific manifestations of DARs that were significantly more frequent at contrast-enhanced CT were skin rash (P = .0311), skin redness (P = .0055), skin swelling (P = .0117), and headache (P = .0246). DARs involving the skin included generalized rashes of the face, neck, chest, back, and extremities and were often associated with swelling, erythema, and pruritus. Conclusion: This study substantiates a frequent occurrence of DARs at contrast-enhanced CT compared with that in control subjects. Continued growth in the use of contrast-enhanced CT suggests a need for greater awareness and attention to prevention and management.