OBJECTIVE. The purpose of this study is to compare sinogram-affirmed iterative reconstruction (SAFIRE) and filtered back projection (FBP) reconstruction of chest CT acquired with 65% radiation dose reduction. MATERIALS AND METHODS. In this prospective study involving 24 patients (11 women and 13 men; mean [± SD] age, 66 ± 10 years), two scan series were acquired using 100 and 40 Quality Reference mAs over a 10-cm scan length in the chest with a 128-MDCT scanner. The 40 Quality Reference mAs CT projection data were reconstructed with FBP and four settings of SAFIRE (S1, S2, S3, and S4). Six image datasets (FBP with 100 and 40 Quality Reference mAs, and S1, S2, S3, S4 with 40 Quality Reference mAs) were displayed on a DICOM-compliant 55-inch 2-megapixel monitor for blinded evaluation by two thoracic radiologists for number and location of lesions, lesion size, lesion margins, visibility of small structures and fissures, and diagnostic confidence. Objective noise and CT values were measured in thoracic aorta for each image series, and the noise power spectrum was assessed. Data were analyzed with analysis of variance and Wilcoxon signed rank tests. RESULTS. All 186 lesions were seen on 40 Quality Reference mAs SAFIRE images. Diagnostic confidence on SAFIRE images was higher than that for FBP images. Except for the minor blotchy appearance on SAFIRE settings S3 and S4, no significant artifacts were noted. Objective noise with 40 Quality Reference mAs S1 images (21.1 ± 6.1 SD of HU) was significantly lower than that for 40 Quality Reference mAs FBP images (28.5 ± 8.1 SD of HU) (p < 0.001). Noise power spectra were identical for SAFIRE and FBP with progressive noise reduction with higher iteration SAFIRE settings. CONCLUSION. Iterative reconstruction (SAFIRE) allows reducing the radiation exposure by approximately 65% without losing diagnostic information in chest CT.