High neuroticism predicts psychopathology and physical health problems. Nongenetic factors, including major life events and experiences, explain approximately half of the variance in neuroticism. Conversely, neuroticism also predicts these life experiences. In this study, we aimed to quantify the reciprocal causation between neuroticism and life experiences and to gauge the magnitude and persistence of these associations. This longitudinal cohort study included 5 assessment waves over 16 years in a random sample of 296 Dutch participants (47% women) with a mean age of 34 years (SD = 12, range 16-63 years). Neuroticism was assessed with the Amsterdam Biographic Questionnaire. The experiences measured included positive and negative life events, long-term difficulties (LTDs), and change in life quality, all assessed by contextual rating procedures adapted from the Life Event and Difficulties Schedule. We fit structural equation models in Mplus. Results showed that neuroticism consistently predicted negative experiences, decreased life quality, and LTDs (β = 0.15 to 0.39), whereas effects on positive experiences were variable (β = 0.14). LTDs and deteriorated life quality each predicted small but persistent increases in neuroticism (β = 0.18), whereas improved life quality predicted small but persistent decreases (β = -0.13). This suggests set point change in neuroticism. Life event aggregates showed no persistent effects on the neuroticism set point. Neuroticism and life experiences showed persistent, bidirectional associations. Experience-driven changes in neuroticism lasted over a decade. Results support the corresponsive principle (reciprocal causation), suggesting a mixed model of change in neuroticism that distinguishes temporary changes in neuroticism from persistent changes in an individual's neuroticism set point.