Recent studies have shown that fat accumulation is associated with insulin resistance; however, the risks associated with long-term changes and fluctuations in central fatness are less clear. This study examined the longitudinal relationship between waist circumference (WC) and insulin resistance using three dimensions of WC: baseline WC, slope of linear changes in WC, and fluctuation of WC around the slope during 20 years of follow-up. Anthropometry, insulin resistance (homeostasis model assessment (HOMA(IR))), and lifestyle factors were obtained in a population-based, prospective observational study (Coronary Artery Risk Development in Young Adults (CARDIA)) during 1985-2006, excluding participants who had been diagnosed with diabetes at any examination. After adjusting for socio-demographic and lifestyle factors, the evolution of HOMA(IR) from CARDIA year 15 to 20 was 6.9% higher per standard deviation of year 0 WC (P trend <0.0001) and 6.3% higher per standard deviation increase in the change in WC over the long term (P trend <0.0001). However, WC fluctuations around the linear change were not associated with insulin resistance or its evolution. The level of HOMA(IR) increased substantially with steeper linear WC slope among initially thinner participants at baseline, whereas this association tended to be weaker in those with higher initial WC (P interaction <0.0001). We conclude that year 0 WC and long-term increment in WC are associated with worsening insulin resistance. However, the association of HOMA(IR) with slope of WC change may vary across the range of initial WC.