Objective. Personality factors moderate self-efficacy enhancing effects of some illness self-management interventions, but their influence on self-rated health is unclear. This study examined whether high neuroticism and low conscientiousness, extraversion, and agreeableness (the distressed personality profile) moderated the effects of the homing in on health (HIOH) illness self-management intervention on mental and physical health status. Design. Analysis of data from 384 subjects completing a randomized controlled trial of HIOH. Methods. Regression analyses examined effects of NEO-five factor inventory scores on SF-36 mental component summary (MCS-36) and physical component summary (PCS-36) scores (baseline; 2, 4, and 6 weeks; 6 months; 1 year), adjusting for age, gender, and study group. Results. Baseline MCS-36 scores were worse in those with the distressed personality profile relative to others: high neuroticism (13.3 points worse, 95% confidence interval (CI) = 11.0, 15.7) and low conscientiousness (6.6 points worse, 95% CI = 4.1, 9.2), extraversion (10.1 points worse, 95% CI = 7.7, 12.5) and agreeableness (4.2 points worse, 95% CI = 1.6, 6.8). Intervention subjects had better MCS-36 scores at 4 and 6 weeks, and benefits were confined to participants with low conscientiousness (4 weeks - 3.7 points better, 95% CI = 0.2, 71; 6 weeks -5.0 points better, 95% CI = 1.57, 8.4). There were no intervention or personality effects on PCS-36 scores. Conclusions. Chronically ill self-management intervention recipients with the distressed personality profile had worse self-rated mental health, and conscientiousness moderated the short-term effects of the intervention on self-rated mental health. Measuring personality may help identify individuals more likely to benefit from self-management interventions.