The relationship between cigarette smoking and cell damage is complicated, particularly considering the role of oxidative stress. The aim of this study was to identify the relationships among plasma nicotine metabolites, lipophilic antioxidants, and metabolic parameters in smokers and nonsmokers. This cross-sectional study recruited 100 subjects who visited the Department of Family Medicine at Kaohsiung Medical University Hospital. Excluding 14 ineligible cases, 46 smokers and 40 non-smokers were enrolled. Plasma nicotine metabolites, lipophilic antioxidants (including retinol, lycopene, alpha-carotene, beta-carotene, delta-tocopherol, gamma-tocopherol and alpha-tocopherol), related metabolic parameters, and body composition (including height, weight, body mass index, body fat, and waist circumference) were examined by comparison of means, correlations and regressions. Significant correlations among nicotine metabolites, age, sex, body composition and plasma lipophilic antioxidants were noted. Nicotine metabolites, age, body height and body weight were closely associated with plasma antioxidant levels (p < 0.05) in multiple linear regression. The levels of alpha-carotene, beta-carotene, gamma-tocopherol and lycopene were lower in smokers than in non-smokers (p < 0.01). The plasma level of high-sensitivity C-reactive protein (hsCRP), which is a marker for high cardiovascular risk, was higher in smokers than in non-smokers (p = 0.003). We conclude that the lower plasma antioxidant levels and the higher level of hsCRP in smokers may lead to decreased protective efficacy compared with non-smokers. Further studies are warranted to support our hypothesis.