Sex differences in levels of C-reactive protein (CRP) are well established in adulthood, but little is known about when and why they emerge. Here, we tested longitudinal models of CRP levels from ages 9 to 21, when marked physical and behavioral changes could contribute to growing sex disparities in CRP. Data from the community-based prospective-longitudinal Great Smoky Mountains Study (N=1420) were used. Participants were 9-13 years old at intake and were followed through age 21. High-sensitivity C-reactive protein (CRP) was assayed from up to nine bloodspot collections per person. BMI, physical/sexual maturation, substance use, and control variables were assessed during yearly interviews to age 16, and at ages 19 and 21. Multilevel models revealed that the development of CRP in females was best described by a quadratic trend: after slow increases in CRP until age 15, the rate of increase accelerated thereafter. Changes in CRP in males were best described by a smaller, linear increase. After sex-differentiated associations with BMI, physical/sexual maturation, and substance use variables had been accounted for, increases in CRP after age 15 no longer differed by sex. Physical/sexual maturation and behavioral changes during adolescence could initiate life-long sex disparities in CRP.