Genetic factors contribute significantly to interindividual differences in the susceptibility to stress-related disorders. As stress can also be conceptualized as environmental exposure, controlled gene-environment interaction (GxE) studies with an in-depth phenotyping may help to unravel mechanisms underlying the interplay between genetic factors and stress. In a prospective-longitudinal quasi-experimental study, we investigated whether polygenic scores (PGS) for depression (DEP-PGS) and neuroticism (NEU-PGS), respectively, were associated with responses to chronic stress in daily life. We examined law students (n = 432) over 13 months. Participants in the stress group experienced a long-lasting stress phase, namely the preparation for the first state examination for law students. The control group consisted of law students without particular stress exposure. In the present manuscript, we analyzed perceived stress levels assessed at high frequency and in an ecologically valid manner by ambulatory assessments as well as depression symptoms and two parameters of the cortisol awakening response. The latter was only assessed in a subsample (n = 196). No associations between the DEP-PGS and stress-related variables were found. However, for the NEU-PGS we found a significant GxE effect. Only in individuals experiencing academic stress a higher PGS for neuroticism predicted stronger increases of perceived stress levels until the exam. At baseline, a higher NEU-PGS was associated with higher perceived stress levels in both groups. Despite the small sample size, we provide preliminary evidence that the genetic disposition for neuroticism is associated with stress level increases in daily life during a long-lasting stress period. In the LawSTRESS project, a study with a prospective-longitudinal quasi-experimental design, German law students experiencing (stress group) or not experiencing (control group) a long-lasting stress phase were examined. We analyzed whether polygenic scores (PGS) for depression and neuroticism, respectively, were associated with perceived stress levels in daily life. For the neuroticism PGS we found a significant GxE effect; only in the stress group a higher PGS predicted stronger increases of perceived stress levels over 13 months.image