Recent evidence suggests that dispositional positive affect may be associated with decreased vulnerability to upper respiratory infections. To explore a potential pathway of this relationship, we examined whether trait positive affect is related to an in vivo immune response relevant for host resistance to infection. Eighty-four healthy, graduate students who tested negative for prior expose to the hepatitis B virus were administered the standard hepatitis B vaccination series. Five months after the first dose, a blood sample was collected for the measurement of specific antibody response to the vaccine and subjects completed a battery of psychosocial questionnaires. Higher scores on a measure of dispositional positive affect were associated with a greater antibody response to hepatitis B vaccination. This relationship occurred after controlling for demographics and body mass and was largely independent of concomitant levels of dispositional negative affect, optimism, and extraversion. In the presence of dispositional positive affect, there was no independent effect of trait negative affect on antibody response. Physical activity played a protective role for individuals low in positive affect, being related to higher antibody responses. These data provide initial evidence that individual differences in dispositional positive affect may be of health significance, being related to an in vivo immune response relevant for protection against infection.