Objectives To validate and evaluate an integrated protocol for non‐invasive prenatal genetic screening (NIPS) for common fetal aneuploidies in a clinical setting, using the semiconductor sequencing technology, Ion Proton. Methods This prospective cohort study included 2505 pregnant women from seven academic genetic laboratories (695 high risk pregnancies in a validation study and 1810 pregnancies with a risk higher than 1/250 without ultrasound anomalies, in a real NIPS clinical setting). Cell free DNA from plasma samples was sequenced using Ion Proton sequencer, and sequencing data were analyzed using the open‐access software WISECONDOR. Performance metrics for detection of trisomies 21, 18 and 13, were calculated based on either fetal karyotype result or clinical data collected at birth. We also evaluated the failure rate and compared three methods of fetal fraction quantification (RASSF1A assay, DEFRAG and SANEFALCON software). Results Sensitivities and specificities were: 98.3% (95%CI: 93.5 ‐ 99.7) and 99.9% (95%CI: 99.4 ‐ 100) for T21, 96.7% (95%CI: 80.9 ‐ 99.8) and 100% (95%CI: 99.6 ‐ 100) for T18, 94.1% (95%CI: 69.2 ‐ 99.7) and 100% (95%CI: 99.6 ‐ 100) for T13. Our failure rate was 1.2% at first and as low as 0.6% after re‐testing some of the failed samples. Fetal fraction estimation by RASSF1A assay was consistent with DEFRAG results, both of which are adequate for routine diagnosis. Conclusions We describe one of the largest studies evaluating the Ion Proton based NIPS and the first clinical study reporting pregnancy outcome in a large set of patients. We demonstrate that this platform is highly efficient in detecting the three most common trisomies. Our protocol is robust and can be easily implemented in any medical genetics laboratory.