Background : Social isolation is known to be associated with poorer health amongst adults, including coronary heart disease. It is hypothesized that this association may be mediated by inflammation. There has been little prospective research on the long-term impact of social isolation in childhood on adult health or the pathways which might be involved. The aim of this study was to investigate whether social isolation in childhood is associated with increased adult inflammation and the mechanisms involved across the life course. Methods : This study used multiply-imputed data on 7462 participants of the National Child Development Study in Great Britain. The association between child social isolation (7–11 yrs) and levels of C-reactive protein (CRP) in middle age (44 yrs) was examined. We additionally investigated the role of adult social isolation, psychological distress, health behaviors and socioeconomic factors as potential mediators using path analysis and concurrent measurements made across the life course. Results : Socially isolated children had higher levels of C-reactive protein in mid-life (standardized coefficient = 0.05, p ≤ 0.001). In addition, children who were socially isolated tended to have lower subsequent educational attainment, be in a less advantaged social class in adulthood, were more likely to be psychologically distressed across adulthood and were more likely to be obese and to smoke. All of these factors partially explained the association between childhood social isolation and CRP. However, this association remained statistically significant after considering all mediators simultaneously. Conclusions : Social isolation in childhood is associated with higher levels of C-reactive protein in mid-life. This is explained in part through complex mechanisms acting across the life course. Identification and interventions targeted toward socially isolated children may help reduce long-term adult health risk.