Class III β-tubulin (TUBB3) is emerging as a biomarker in a number of cancers. TUBB3 has been shown to be a prognostic indicator of more aggressive disease and a predictor of resistance to taxanes and vinca alkaloids. To date, there is little data on TUBB3 expression in small cell lung carcinoma (SCLC). The primary objective of this study was to determine the expression of TUBB3 in SCLC. Immunohistochemical staining of SCLC tumor specimens was performed using standard procedures. Expression of TUBB3 was determined as a composite of the percentage of malignant cells staining positive and the intensity of staining. Clinical and tumor data for each patient was compared with the degree of TUBB3 expression. A total of 66 SCLCs were evaluable for TUBB3 expression. The majority of specimens (n=56, 85%) had high expression of TUBB3. Only 4.5% (n=3) had low expression of TUBB3. The mean distribution of positive staining for the specimens was 87.3±1.8% (mean ± SE). Specimens from core biopsies were significantly more likely to have high TUBB3 expression when compared with fine needle aspirates (P=0.004). There were no other significant findings when comparing clinical or tumor characteristics. Overall, we found that expression of TUBB3 in SCLC is higher than expected. Innate resistance to microtubule inhibitors, such as the taxanes and vinca alkaloids, may be associated with this finding. Attempts at microtubule inhibition with novel agents may be able to overcome this resistance mechanism. Further evaluation of TUBB3 as a biomarker in SCLC is warranted.