1523 Background: Low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in the National Lung Screening Trial (NLST). The efficacy of LDCT screening could be improved by targeting smokers at highest risk of lung cancer death, provided that the efficacy of LDCT screening increases with lung cancer mortality risk. Methods: We evaluated the efficacy of LDCT screening as compared to chest radiography in the NLST across groups defined by participants’ 5-year risk of lung cancer mortality at randomization, which was estimated using a validated prediction model. Across quintiles of 5-year lung cancer mortality risk [Q1: 0.15%-0.55%, Q2: 0.56%-0.84%, Q3: 0.85%-1.24%, Q4: 1.24%-2.0%, Q5: >2.0%], we estimated the number of participants with false positive screens, the number of prevented lung cancer deaths, and their ratio. Results: The number of prevented lung cancer deaths due to LDCT screening increased in tandem with lung cancer mortality risk (Q1=0.2, Q2=3.5, Q3=5.1, Q4=11.0, Q5=12.0 per 10,000 person-years; P-trend=0.01). The number of participants with false positive screens per lung cancer death prevented, a measure of screening efficiency, significantly decreased with increasing risk (Q1=1,648, Q2=181, Q3=147, Q4=64, Q5=65, P-trend<0.001). The 60% of participants at highest 5-year lung cancer mortality risk (0.85% or greater) accounted for 88% of LDCT-preventable lung cancer deaths and included only 64% of participants with a false positive screen. The 20% of participants at lowest lung cancer mortality risk (0.15%-0.55%) accounted for only 1% of LDCT-preventable lung cancer deaths. Conclusions: In the NLST, LDCT screening prevented the most lung cancer mortality among those at highest lung cancer mortality risk and prevented almost no mortality among those at lowest risk, providing empirical support for risk-based targeting of smokers to improve the efficacy of LDCT screening.