Background/aim: The aim of this study was to assess unnecessary immunization rates and compare the cost-effectiveness of targeted prophylaxis with fetal Rh genotyping with that of traditional management of Rh-Rh incompatibility in a virtual economic model. Materials and methods: This retrospective data analysis was conducted at two tertiary centers between 2011 and 2015. The data of 1135 pregnant women were analyzed. The main outcome measure was to determine the unnecessary immunization rate among the whole Rh-Rh incompatibility group. The second outcome measure was to compare the cost-effectiveness of universal immunization with that of targeted prophylaxis with fetal Rh genotyping in a virtual economic model. Results: Average cost per patient was found as $\$$259.20 with universal prophylaxis and the total cost was $\$$177,344, whereas if targeted prophylaxis had been applied to these patients the total cost would have been $\$$263,392 and cost per patient would have been $\$$385. Universal prophylaxis was more cost-effective than targeted prophylaxis in terms of both total cost and cost per patient (P < 0.0001). Conclusion: Unless the cost of noninvasive fetal Rh genotyping is reduced, a universal approach of anti-D immune globulin prophylaxis is more cost-effective than noninvasive determination of fetal Rh genotyping with targeted prophylaxis.