Background: Deep learning image reconstruction (DLIR) improves image quality. We aimed to compare the measured diameter of pulmonary lesions and lymph nodes between DLIR-based ultra-low-dose CT (ULDCT) and contrast-enhanced CT. Methods: The consecutive adult patients with noncontrast chest ULDCT (0.07–0.14 mSv) and contrast-enhanced CT (2.38 mSv) were prospectively enrolled. Patients with poor image quality and body mass index ≥ 30 kg/m2 were excluded. The diameter of pulmonary target lesions and lymph nodes defined by Response Evaluation Criteria in Solid Tumors (RECIST) was measured. The measurement variability between ULDCT and enhanced CT was evaluated by Bland-Altman analysis. Results: The 141 enrolled patients (62 ± 12 years) had 89 RECIST-defined measurable pulmonary target lesions (including 30 malignant lesions, mainly adenocarcinomas) and 45 measurable mediastinal lymph nodes (12 malignant). The measurement variation of pulmonary lesions between high-strength DLIR (DLIR-H) images of ULDCT and contrast-enhanced CT was 2.2% (95% CI: 1.7% to 2.6%) and the variation of lymph nodes was 1.4% (1.0% to 1.9%). Conclusions: The measured diameters of pulmonary lesions and lymph nodes in DLIR-H images of ULDCT are highly close to those of contrast-enhanced CT. DLIR-based ULDCT may facilitate evaluating target lesions with greatly reduced radiation exposure in tumor evaluation and lung cancer screening.