The present study evaluated the singular and interactive effects of a functional polymorphism (variation) in the serotonin transporter (5-HTT) gene and a psychological trait (anxiety sensitivity [AS], i.e., fear of arousal symptoms) in predicting subjective and physiological responses to a 35% carbon dioxide (CO2) challenge in a community sample (N = 72). Genotypes were divided into 2 groups in accord with prior research. Findings were partially supportive of the hypothesized risk model. These indicated that the Group L genotype (homozygous for the 1 allele), compared with the Group S genotype (homozygous for the s allele plus heterozygous individuals), predicted greater fearful response to the biological challenge. There was also an AS x Genotype interaction predicting heart rate variability (HRV) in response to the CO2, suggesting that high AS plus Group L status predicts decreased HRV.