Purpose To investigate performance in detectability of small (≤1 cm) low-contrast hypoattenuating focal lesions by using filtered back projection (FBP) and iterative reconstruction (IR) algorithms from two major CT vendors across a range of 11 radiation exposures. Materials and Methods A low-contrast detectability phantom consisting of 21 low-contrast hypoattenuating focal objects (seven sizes between 2.4 and 10.0 mm, three contrast levels) embedded into a liver-equivalent background was scanned at 11 radiation exposures (volume CT dose index range, 0.5-18.0 mGy; size-specific dose estimate [SSDE] range, 0.8-30.6 mGy) with four high-end CT platforms. Data sets were reconstructed by using FBP and varied strengths of image-based, model-based, and hybrid IRs. Sixteen observers evaluated all data sets for lesion detectability by using a two-alternative-forced-choice (2AFC) paradigm. Diagnostic performances were evaluated by calculating area under the receiver operating characteristic curve (AUC) and by performing noninferiority analyses. Results At benchmark exposure, FBP yielded a mean AUC of 0.79 ± 0.09 (standard deviation) across all platforms which, on average, was approximately 2% lower than that observed with the different IR algorithms, which showed an average AUC of 0.81 ± 0.09 (P = .12). Radiation decreases of 30%, 50%, and 80% resulted in similar declines of observer detectability with FBP (mean AUC decrease, -0.02 ± 0.05, -0.03 ± 0.05, and -0.05 ± 0.05, respectively) and all IR methods investigated (mean AUC decrease, -0.00 ± 0.05, -0.04 ± 0.05, and -0.04 ± 0.05, respectively). For each radiation level and CT platform, variance in performance across observers was greater than that across reconstruction algorithms (P = .03). Conclusion Iterative reconstruction algorithms have limited radiation optimization potential in detectability of small low-contrast hypoattenuating focal lesions. This task may be further complicated by a high degree of variation in radiologists' performances, seemingly exceeding real performance differences among reconstruction algorithms. © RSNA, 2018 Online supplemental material is available for this article.