The Food and Drug Administration’s (FDA) The Real Cost campaign advertisements (ads) have targeted U.S. youth with messages designed to prevent and reduce tobacco use. This study examined exposure to The Real Cost campaign, including ad and slogan recall, and associations with attitudes and risk perceptions among U.S. adolescents. We analyzed data from a nationally representative sample of adolescents aged 13 to 17 years (n = 1125) surveyed by phone from October 2014 to June 2015. We assessed aided recall of and attitudes toward four campaign ads and the one slogan. Logistic regression models assessed whether aided recall of The Real Cost ads or slogan was associated with perceived likelihood of serious health consequences of cigarette smoking. Most (88%) adolescents reported seeing or hearing at least one of four ads for The Real Cost, and 54% recalled The Real Cost slogan. The majority of adolescents reported more negative attitudes toward tobacco products after seeing or hearing the ads. Recall of any The Real Cost ad was significantly associated with greater perceptions of serious health consequences of cigarette smoking (Adjusted Odd Ratios (AOR) = 5.58, 95% Confidence Interval (CI) = 1.20–25.90). The FDA’s The Real Cost campaign has achieved very high reach and is associated with more negative attitudes toward tobacco products and greater risk perceptions of cigarette smoking among U.S. adolescents