In recent years, a growing popularity of carbon dioxide (CO2) as a secondary fluid has been witnessed in both forced as well as in natural circulation loops (NCLs). This may be attributed to the favorable thermophysical properties of CO2 in addition to the environmental benignity of the fluid. However, an extensive literature review shows that studies on CO2-based NCLs are very limited. Also, most of the studies on NCLs do not consider the three-dimensional variation of the field variables. In the present work, three-dimensional computational fluid dynamics (CFD) models of a NCL with isothermal source and sink have been developed to study the effect of tilt angle in different planes. Studies have been carried out employing subcritical (liquid and vapor) as well as supercritical phase of CO2 as loop fluid at different operating pressures and temperatures. Results are obtained for a range of tilt angles of the loop, and a significant effect is observed on heat transfer, mass flow rate, and stability of the loop. It was also found that changing the orientation of the loop could be an elegant and effective solution to the flow instability problem of NCLs.