The implications of a persistent "non-diagnostic" fine needle aspiration biopsy (FNAB) has yet to be defined in patients with a solitary thyroid nodule. Four hundred and eleven patients from 1986 to 1990 with a solitary cold thyroid nodule underwent thyroidectomy, including 92 with a "non-diagnostic" FNAB, despite a minimum of two repeat samples. Pathology revealed cancer in eight (9%)--six papillary, one lymphoma, and one squamous cell--follicular adenoma in 38 (41%), Hurthle cell adenoma in two (2%), colloid nodule in 41 (45%), epithelial cyst in two (2%), and thyroiditis in one patient (1%). The operation was uncomplicated by hypoparathyroidism or nerve dysfunction. Age, sex, nodule size, and a history of neck irradiation were examined as possible predictors of cancer risk. Male sex, previous neck irradiation and larger nodules were more common among thyroid cancer patients, but only male sex was statistically significant (P < 0.05). Persistent "nondiagnostic" cytology is a significant limitation of FNAB associated with a 52% neoplasia rate and a 9% incidence of malignancy. "Non-diagnostic" FNAB should be repeated and, if necessary, performed under ultrasound guidance. In order to avoid a missed carcinoma, surgical treatment of persistent "non-diagnostic" FNAB in a dominant hypofunctioning nodule is indicated for the male patient, radiation-associated nodular thyroid disease, recurrent cysts, compression symptoms, and failure of a 6-month trial of thyroid suppression. Lack of needle biopsy and operative morbidity justifies the aggressive exclusion of cancer.