Objective: To evaluate cell‐free DNA (cfDNA) testing as a non‐invasive approach to detecting aneuploidies in clinical miscarriages. Design: A retrospective cohort study of women with pregnancy loss. Setting: Hospitals and genetic analysis laboratories. Population or sample: Pregnancy losses in the period 2021–2022. Methods: Results derived from non‐invasive cfDNA testing (Veriseq NIPT Solution V2) of maternal blood and invasive analysis of products of conception (POC) (Ion ReproSeq) compared in 120 women who suffered a miscarriage. Main outcome measures: Concordance rate results, cfDNA testing performance, non‐informative rate (NIR) and fetal fraction (FF). Results: We found no significant differences in the NIR between invasive (iPOC) and non‐invasive (niPOC) analysis of POC (10.0% [12/120] versus 16.7% [20/120]). Of 120 samples, 90 provided an informative result in iPOC and niPOC groups (75%). cfDNA analysis correctly identified 74/87 (85.1%) samples (excluding triploidies). Sensitivity and specificity were 79.4% and 100%, respectively; all discordant cases were female. A binomial logistic model suggested fetal sex as the only variable influencing the concordance rate (P = 0.035). A Y‐chromosome‐based FF estimate allowed the optimal reclassification of cfDNA of non‐informative male fetuses and a more accurate evaluation of cfDNA testing performance. The difference between the two FF estimates (native algorithm and Y‐chromosome‐based) suggests that female non‐concordant cases may represent non‐informative cases. Conclusions: Cell‐free DNA‐based testing provides a non‐invasive approach to determining the genetic cause of clinical miscarriage. [ABSTRACT FROM AUTHOR]