Purpose <p>Ample research exists on the association of migration status and health-related quality of life (HRQoL). Specific personality traits linked to the Big Five such as neuroticism, have been found to be predictive of migrants’ intercultural success. This study aimed to analyze the moderating effect of neuroticism on migration status and HRQoL in a representative German sample.</p> Methods <p>Data from the German Socioeconomic Panel (GSOEP) (<i>N</i> = 29,968) were analyzed. The sample included Germans without migration background (<i>n</i> = 19,749), immigrants (<i>n</i> = 3,491), foreigners residing in Germany (<i>n</i> = 2,460), and refugees (<i>n</i> = 4,268). Gender-stratified moderation analyses were performed using General Linear Models with HRQoL (SF-12; mental and physical health) as outcome, migration status as predictor, and neuroticism (BFI-S) as moderator.</p> Results <p>Refugees reported the lowest HRQoL (<i>F</i>(3, 29192) = 27.54, <i>p</i> &lt;.001). Refugees also displayed the lowest neuroticism scores. Significant moderation effects of neuroticism on the relationship between migration status and SF-12 mental HRQoL scores were observed, especially for refugees (β = 0.05, <i>CI</i> [0.01 – 0.10], <i>p</i> =.03) and immigrants (β = 0.04, <i>CI</i> [0.00 – 0.08], <i>p</i> =.03; <i>R²</i> = 0.064). Women had lower SF-12 scores compared to men across all groups. Additionally, there was a significant three-way interaction effect for female refugees with neuroticism on mental HRQoL (β = − 0.24; <i>CI</i> [-0.34 – − 0.14]; <i>p</i> &lt;.001).</p> Conclusion <p>The results corroborated research pointing out differences in HRQoL depending on migration status and gender. Refugees seem to benefit particularly from low neuroticism, in terms of emotional stability, as a psychological resource.</p>