Background High neuroticism is prospectively associated with psychopathology and physical health. However, within-subject changes in neuroticism due to life experiences (LEs) or state effects of current psychopathology are largely unexplored. In this 2-year follow-up study, four hypotheses were tested:(1) positive LEs (PLEs) decrease and negative LEs (NLEs) increase neuroticism; (2) LE-driven change in neuroticism is partly long-lasting; and (3) partly independent of LE-driven changes in anxiety/depression; and (4) childhood adversity (before age 16 years) moderates the influence of NLEs/PLEs on neuroticism scores in adult life. Method Data came from the Netherlands Study of Depression and Anxiety [NESDA, n = 2981, mean age 41.99 years (s.d. = 13.08), 66.6% women]. At follow-up (T 2) we assessed PLEs/NLEs with the List of Threatening Experiences (LTE) over the prior 24 months and categorized them over recent and distant PLE/NLE measures (1-3 and 4-24 months prior to T 2 respectively) to distinguish distant NLE/PLE-driven change in trait neuroticism (using the Dutch version of the Neuroticism- Extroversion-Openness Five Factor Inventory, NEO-FFI) from state deviations due to changes in symptoms of depression (self-rated version of the 30-item Inventory of Depressive Symptomatology, IDS-SR30) and anxiety (Beck Anxiety Inventory, BAI). Results Distant NLEs were associated with higher and distant PLEs with lower neuroticism scores. The effects of distant LEs were weak but long-lasting, especially for distant PLEs. Distant NLE-driven change in neuroticism was associated with change in symptoms of anxiety/depression whereas the effect of distant PLEs on neuroticism was independent of any such changes. Childhood adversity weakened the impact of distant NLEs but enhanced the impact of distant PLEs on neuroticism. Conclusions Distant PLEs are associated with small but long-lasting decreases in neuroticism regardless of changes in symptom levels of anxiety/depression. Long-lasting increases in neuroticism associated with distant NLEs are mediated by anxiety/depression. © 2013 Cambridge University Press .