<b><i>Background:</i></b> Analysis of cell-free fetal DNA in maternal plasma is very promising for early diagnosis of monogenic diseases. However, it has been limited by the need to set up patient- or disease-specific custom-made approaches. Here we propose a universal test based on fluorescent multiplex PCR and size fragment analysis for an indirect diagnosis of cystic fibrosis (CF). <b><i>Methods:</i></b> The test, based on haplotyping, includes nine intra- and extragenic short tandem repeats of the <i>CFTR</i> locus, the coamplification of p.Phe508del (the most frequent mutation in CF patients worldwide), and a specific <i>SRY</i> sequence. The assay is able to determine the inherited paternal allele. <b><i>Results:</i></b> Our simple approach was successfully applied to 30 couples and provided clear results from the maternal plasma. The mean rate of informative markers was sufficient to propose it for use in indirect diagnosis. <b><i>Conclusions:</i></b> This noninvasive prenatal diagnosis test, focused on indirect diagnosis of CF, offers many advantages over current methods: it is simple, rapid, and cost-effective. It allows for the testing of a large number of couples with high risk of CF, whatever the familial mutation of the <i>CFTR</i> gene. It provides an alternative method to reduce the number of invasive tests.