Comparative genomic hybridization (CGH) has been used for a genome-wide screening of genetic imbalances in tumours. As CGH to chromosomes is technically difficult and yields only limited resolution, the chromosome targets were replaced by arrays of defined DNA fragments, an approach termed matrix-CGH. We have developed a protocol which allows detection of low copy-number gains and losses of genomic segments more than 75 kb in size, improving the resolution of CGH by two orders of magnitude. High-level amplifications are reliably detected with targets of cosmid size. Detection of high-level amplifications is also achived when tumour test DNA is amplified by a universal PCR procedure due to the limited amount of source material. On automation of the matrix-CGH procedure1, we have focused on the development of a disease-specific chip for the diagnosis of recurrently imbalanced regions in chronic lymphocytic leukaemia of B-cell type (B-CLL). The profile of genomic imbalances in B-CLL had been previously assessed in a large series of tumours. DNA fragments from recurrently imbalanced regions were isolated and immobilized on a glass surface. This chip was applied for a screening in a series of B-CLL tumours. Comparison of data obtained by matrix-CGH and interphase cytogenetics revealed a specificity of more than 95% of matrix-CGH. To further increase the sensitivity and specificity, the chip was modified by including additional targets from the respective regions to obtain redundant informations for the relevant loci. The usefulness of chip-based genomic and expression profiling in B-CLL will be discussed.