OBJECTIVE To evaluate the diagnostic performance of full-field slot-scan charge-coupled device (CCD)-based digital radiography in the detection of simulated chest diseases in clinical conditions versus that of two screen-film techniques: advanced multiple beam equalization radiography (AMBER) and Bucky radiography. METHODS Simulated nodules and interstitial nodular and interstitial linear lesions were attached onto an anthropomorphic chest phantom. One hundred sixty-eight lesions were distributed over 25 configurations. A posteroanterior chest radiograph of each configuration was obtained with each technique. The images were presented to six observers. Each lesion was assigned one of two outcome scores: "detected" or "not detected." False-positive readings were evaluated. Differences between the imaging methods were analyzed by using a semiparametric logistic regression model. RESULTS For simulated nodules and interstitial linear disease, no statistically significant difference was found in diagnostic performance between CCD digital radiography and AMBER. The detection of simulated interstitial nodular disease was better with CCD digital radiography than with AMBER: Sensitivity was 71% (77 of 108 interstitial nodular lesions) with CCD digital radiography but was 56% (60 of 108 lesions) with AMBER (P =.041). Better results for the detection of all lesion types in the mediastinum were observed with CCD digital radiography than with Bucky screen-film radiography: Sensitivity was 45% (227 of 504 total simulated lesions) with CCD digital radiography but was 24% (119 of 504 lesions) with Bucky radiography (P <.001). There were fewer false-positive observations with CCD digital radiography (35 [5.7%] of 609 observations) than with Bucky radiography (47 [9.5%] of 497 observations; P =.012). CONCLUSIONS Differences were in favor of the full-field slot-scan CCD digital radiographic technique. This technique provides a digital alternative to AMBER and Bucky screen-film radiography.