BACKGROUND Injection drug use is the most frequently reported risk behavior among new cases of hepatitis C virus infection, and recent reports of increases in infection are of great concern in many communities. This study assessed the prevalence and trends in injection drug use among U.S. high school students. METHODS Data were from CDC's Youth Risk Behavior Surveillance System, which collects information on health risk behaviors at the national, state, and large urban school district levels. Analyses were conducted in 2014. RESULTS In 2013, 1.7% of high school students nationwide had ever injected any illegal drug. Nationwide, ever injecting any illegal drug did not change significantly from 1995 to 2013, except among black non-Hispanic students. For this subgroup, both a significant linear increase from 1995 to 2013 and a significant quadratic trend were observed, with injection drug use increasing from 1995 to 2009 and decreasing from 2009 to 2013. Significant linear increases in injection drug use occurred in five states (Arkansas, Hawaii, Maine, Maryland, and New York) and six large urban school districts (Baltimore, Memphis, Miami-Dade County, New York City, Philadelphia, and Seattle). Significant linear decreases occurred in three states (Massachusetts, South Dakota, and West Virginia). Both a significant linear increase and quadratic trend were observed in Maine; quadratic trends were observed in Tennessee, Utah, and Palm Beach County, Florida. CONCLUSIONS In some geographic areas and population groups, an increasing or high frequency of injection drug use was found among high school students, who should be targeted for prevention.