Smoking negatively affects serum carotenoid levels, and it is a negative prognostic factor for head and neck cancer. In this study, micronutrient levels were examined in 60 smoking and non-smoking head and neck cancer patients. The goal was to determine if oxidation of the carotenoid lycopene would occur to a greater extent in smokers. Subjects were drawn from a prospective cohort study and matched on seven demographic factors. Serum levels of α-carotene, zeaxanthin, and 2,6-cyclolycopene-1,5-diol A, an oxidation product of lycopene, were all lower in smokers versus non-smokers (18%, 22%, and 8%, respectively) while β-carotene, β-cryptoxanthin, and lutein were about the same in the two groups. Levels of lycopene, γ-tocopherol, and α-tocopherol were higher in smokers, and notably serum α-tocopherol was 48% higher in smokers. The majority of vitamin E intake was from supplements. The higher levels of α-tocopherol in smokers were interesting in that higher α-tocopherol levels have been associated with higher mortality in head and neck cancer. Although this was a pilot investigation, there was no evidence that 2,6-cyclolycopene-1,5-diol A formation was appreciably affected by smoking status, but α-tocopherol levels were higher in smokers.