Purpose: Low-cost resin 3D printers have been used to produce affordable interim single crowns in public and private dental practices. The purpose of this study was to assess the impact of different computer-aided design (CAD) software programs on 3D trueness, microscopic marginal and internal gaps, time to design, and interproximal contacts of low-cost 3D-printed single crowns. Materials and Methods: This in vitro study was performed on a total of 90 standardized resin-prepared teeth adapted to a dental manikin. For comparison among CAD software programs, 45 tooth preparations received 3D-printed crowns designed with one of three CAD software programs by an experienced technician and identified as groups TRIOS (n = 15), EXOCAD (n = 15), and ZZ (Zirkonzahn; n = 15). To assess interoperator reproducibility, 15 additional crowns were designed by a dental clinician (group ZZ-DENT) and 15 by a dental prosthetic technician (group ZZ-PROS), both with basic 1-week CAD/CAM training. Finally, as a control group, 15 crowns were milled using a high-end five-axis milling device (group ZZ-CONTROL). Statistically significant differences for 3D trueness, microscopic gaps, time to design, and interproximal contacts among groups were assessed with the Kruskal-Wallis test. Results: No statistically significant differences in 3D trueness or marginal or internal gaps were found, either among different software programs or CAD operators (P > .05). However, Group TRIOS took significantly longer to design than EXOCAD and ZZ groups (P = .001). Less-experienced operators were significantly outperformed in time and interproximal contacts (P = .001) by the CAD technician using the same software program. Finally, control milled crowns (ZZ-CONTROL) significantly outperformed the respective 3D-printed copies (ZZ) in all assessed variables (P < .001). Conclusions: Different CAD software programs may affect the time required to design, but they do not significantly affect clinical outcomes of low-cost 3D-printed resin crowns if designed by an experienced CAD technician.