Background: The link between the diagnostic yield of thyroid fine-needle aspiration and biopsy (FNAB) in patients taking antithrombotic or anticoagulant medications (AT/AC) remains poorly characterized. Objectives: We studied the risk of obtaining a nondiagnostic sample with ultrasound-guided thyroid FNAB in patients taking AT/AC medications. Methods: This is a retrospective cohort study using medical records of 556 patients who underwent thyroid FNAB. All cytology samples were reported using the Bethesda classification. For patients with a nondiagnostic cytology, logistic regression was used to calculate OR for patients taking AT/AC medications. Multivariate regression was used to adjust for potential confounding variables including age, cystic ultrasound features, presence of eggshell calcifications, number of passes performed, cystic aspirate on FNAB, and position of the nodule. Results: Out of 556 patients, cytology results were available for 547 patients. Of these, 46 subjects were taking aspirin and 1 was on warfarin. Among the entire cohort, 17.5% of the subjects had a nondiagnostic cytology. Among the patients on AT/AC medications, 34% had a nondiagnostic result compared to 16% for those not taking them (OR = 2.70, p = 0.003). The subgroup of patients taking aspirin had similarly higher odds of a nondiagnostic cytology (OR = 2.78, p = 0.002). These differences remained statistically significant after multivariate adjustment. Conclusions: This is the first study to demonstrate a 3-fold independently greater risk of a nondiagnostic FNAB cytology in patients taking aspirin. Our results highlight the importance of evaluating the need for continuation of aspirin in patients undergoing thyroid FNAB as this may impact the diagnostic yield of the procedure.