Inflammation and insulin resistance play crucial roles in the development of type 2 diabetes mellitus (T2DM). We aim to examine the temporal relationship between high-sensitivity C-reactive protein (hsCRP) and insulin resistance in non-diabetic adults and their joint effect on the development of hyperglycemia.The longitudinal cohort from the Bogalusa Heart Study consisted of 509 non-diabetic adults (360 whites and 149 blacks, mean age = 42.8 years at follow-up) who had hsCRP, fasting glucose and insulin measured twice at baseline and follow-up over 6.8 years. Cross-lagged panel model was used to examine the temporal relationship between hsCRP and homeostasis model assessment for insulin resistance (HOMA-IR). Information on incident T2DM was collected in a survey in 6.1 years after the follow-up survey.After adjusting for race, sex, age, body mass index, smoking, alcohol drinking and follow-up years, the path coefficient from baseline hsCRP to follow-up HOMA-IR (β = 0.105, p = 0.009) was significant and greater than the path from baseline HOMA-IR to follow-up hsCRP (β = 0.005, p = 0.903), with p = 0.011 for the difference between β and β. This one-directional path from baseline hsCRP to follow-up HOMA-IR was significant in the hyperglycemia group but not in the normoglycemia group. In addition, participants with high levels of baseline hsCRP and follow-up HOMA-IR had greater risks of T2DM (odds ratio, OR = 2.38, p = 0.035), pre-T2DM (OR = 2.27, p = 0.006) and hyperglycemia (OR = 2.18, p = 0.003) than those with low-low levels.These findings suggest that elevated hsCRP is associated with future insulin resistance in non-diabetic adults, and their joint effect is predictive of the development of T2DM.