© 2016 by the American Association for the Study of Liver Diseases Although surveillance ultrasound and alpha fetoprotein (AFP) tests have minimal direct harm, downstream harms from follow-up tests must be weighed against surveillance benefits when determining the value of hepatocellular carcinoma (HCC) screening programs. Our study's aims were to characterize prevalence and correlates of surveillance benefits and harms in cirrhosis patients undergoing HCC surveillance. We conducted a retrospective cohort study among patients with cirrhosis followed at a safety-net health system between July 2010 and July 2013. We recorded surveillance-related benefits, defined as early tumor detection and curative treatment, and surveillance-related physical harms, defined as computed tomography or magnetic resonance imaging scans, biopsies, or other procedures performed for false-positive or indeterminate surveillance results. Sociodemographic and clinical correlates of surveillance harms were evaluated using multivariable logistic regression. We identified 680 patients with cirrhosis, of whom 78 (11.5%) developed HCC during the 3-year study period. Of the 48 (61.5%) HCCs identified by surveillance, 43.8% were detected by ultrasound, 31.2% by AFP, and 25.0% by both surveillance tests. Surveillance-detected patients had a higher proportion of early HCC (70.2% vs. 40.0%; P = 0.009), with no difference in tumor stage between ultrasound- and AFP-detected tumors (P = 0.53). Surveillance-related physical harms were observed in 187 (27.5%) patients, with a higher proportion of ultrasound-related harm than AFP-related harm (22.8% vs. 11.4%; P < 0.001). Surveillance-related harms were associated with elevated ALT (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.26-2.76), thrombocytopenia (OR, 2.06; 95% CI, 1.26-3.38), and hepatology subspecialty care (OR, 1.63; 95% CI, 1.09-2.42). Conclusion: Over one fourth of patients with cirrhosis experience physical harm for false-positive or indeterminate surveillance tests—more often related to ultrasound than AFP. Interventions are needed to reduce surveillance-related harm to increase the value of HCC screening programs in clinical practice. (Hepatology 2017;65:1196-1205).