Abstract Study question What carrier screening test is better to reduce the risk of offspring being affected by recessive diseases when genetic matching is performed with gamete donors: complete or targeted genes analysis? Summary answer The use of complete genes analysis in the carrier screening of gamete donors reduces the risk of offspring being affected by recessive diseases. What is known already Legislative measures and scientific societies alike call for more research to be conducted into recessive diseases in gamete donors, in order to reduce reproductive risk. However, it is still unclear which genes should be studied and what type of data analysis, targeted or nontargeted, should be performed. Study design, size, duration This descriptive observational study of 923 oocyte donors and 895 semen donors was conducted from January 2017 to August 2020, at a private gamete bank. Participants/materials, setting, methods 1818 gamete donors screened by NGS and nontargeted analysis of the variants, the pathogenic variants detected were analysed to estimate the probability of high-risk genetic matching and to determine the results that would have been obtained if the three most commonly used genotyping tests for carriers of recessive diseases in ART had been applied. Main results and the role of chance The probability of high-risk genetic matching with gamete donation, screened by NGS and complete genes analysis, was 5.48%, versus the 0.57–2.8% that would have been obtained if the genotyping test had been applied. Of the 1739 total variants found, only 28.69% would have been detected by all three targeted tests considered and 45.66% of the variants would not have been detected by any of them. Limitations, reasons for caution The study was not based in the general population, was limited to a population of Mediterranean ethnic origin. In addition, our study only analysed 302 recessive diseases of the 1,300 plus that have been described. Wider implications of the findings: Our study highlights the considerable heterogeneity of the genotyping tests commonly used in ART, which present significant differences in their ability to detect pathogenic variants. Therefore, the use of genotyping tests for genetic matching is associated with a higher reproductive risk, compared to the use of complete genes analysis. Trial registration number Not applicable