OBJECTIVE: The negative affective response to daily life stressors, which previous work suggest is a fundamental depression endophenotype, may be moderated by positive emotions. It was investigated whether positive affect (PA) buffers negative affect (NA) reactivity in response to stress and whether PA moderates the genetic predisposition to negative affect reactivity. METHOD: A total of 279 twin pairs participated in a momentary assessment study with the experience sampling method, collecting appraisals of stress and affect in the flow of daily life. Lifetime diagnoses of depression were obtained. RESULTS: There was a significant interaction between stress appraisal of event (STRESS) and PA in the association with NA. The interaction between proband PA, proband STRESS and co-twin lifetime depression showed that higher PA reduced the interaction between proband STRESS and co-twin lifetime depression. CONCLUSION: Positive emotions not only buffer against NA reactivity, but in addition attenuate genetic effects on negative mood bias in daily life.