In 1999, mutations in the X‐linked gene methyl‐CpG‐binding protein 2 (MECP2) were first reported in patients with Rett syndrome (RTT). The MECP2 gene is located at Xq28 and consists of 4 exons. About 80–90 % of the classic RTT patients harbor mutations in the coding region of MECP2, while the molecular cause is unknown in the remaining 10–20%. Several groups have searched for large rearrangements within the MECP2 and the results indicate that a fraction of MECP2‐negative RTT cases has large deletions of the MECP2. In this study we have used the Multiplex Ligation‐dependent Probe Amplification (MLPA) technique to screen 45 RTT patients, who have previously been tested negative for mutations in the coding region of MECP2. The MECP2‐MLPA is a semi‐quantitative multiplex PCR approach. It determines the relative number of copies of each MECP2 exon. With this approach we detected seven RTT patients with genomic deletions and further characterized the deletions using real time quantitative PCR (qPCR) and long‐range PCR. The seven patients were given a severity score and their X chromosome inactivation profiles were determined in order to identify a possible genotype‐phenotype correlation. The results from this study indicate that large deletions in MECP2 cause classic RTT.