Most patients with an interstitial deletion of 6q16 have Prader-Willi-like phenotype, featuring obesity, hypotonia, short hands and feet, and developmental delay. In all reported studies, the chromosome rearrangement was detected by karyotype analysis, which provides an overview of the entire genome but has limited resolution. Here we describe a detailed clinical presentation of five patients, two of whom were previously reported, with overlapping interstitial 6q16 deletions and Prader-Willi-like phenotype. Our patients share the following main features with previously reported cases: global developmental delay, hypotonia, obesity, hyperphagia, and eye/vision anomalies. All rearrangement breakpoints have been accurately defined through array-CGH at about 100 Kb resolution. We were able to narrow the shortest region of deletion overlap for the presumed gene(s) involved in the Prader-Willi-like syndrome to 4.1 Mb located at 6q16.1q16.2. Our results support the evidence that haploinsufficiency of the SIM1 gene is responsible for obesity in these patients. A possible involvement of the GRIK2 gene in autistic-like behaviour, of POPDC3 in heart development, and of MCHR2 in the control of feeding behaviour and energy metabolism is also hypothesized.