The risk of miscarriage after chorionic villus sampling (CVS) and amniocentesis (AC) was investigated in randomized clinical trials in the 1980s and 1990s. Studies have compared CVS with AC and found comparable risk of miscarriage after the 2 procedures. Since then, prenatal screening has changed from being based on maternal age to combined first-trimester screening (cFTS) for trisomy 21. The aim of the study was to assess prospectively the risk of fetal loss associated with CVS and AC after cFTS for Down syndrome. A nationwide population-based study (Danish Fetal Medicine Database, 2008–2010) was conducted in which 147,987 women with singleton pregnancy who underwent cFTS participated. The risk of fetal loss with and without invasive testing was assessed using propensity score stratification. Analyses were performed between 3 and 21 days after cFTS for CVS and between 28 and 42 days after cFTS for AC. Results of the study indicated that the risks of miscarriage and stillbirth were not higher in women exposed to CVS or AC compared with unexposed women, independent of the analysis time point. Average effect of CVS on risk of miscarriage was -0.08% (95% confidence interval [CI], -0.64 to 0.47) at 3 days and -0.21% (95% CI, -0.58 to 0.15) at 21 days after cFTS, whereas the effect on risk of stillbirth was -0.18% (95% CI, -0.50 to 0.13) at 3 days and -0.27% (95% CI, -0.58 to 0.04) at 21 days after cFTS. Regarding the effect of AC on risk of miscarriage, the analysis at 28 days after cFTS showed an average effect of 0.56% (95% CI, -0.21 to 1.33), whereas the effect on risk of stillbirth was 0.09% (95% CI, -0.39 to 0.58) at 42 days after cFTS. The study concludes that neither CVS nor AC was associated with increased risk of miscarriage or stillbirth. Findings of the study also indicate that the procedure-related risk of CVS and AC is very low.