Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosome instability and predisposition to develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Clonal chromosome aberrations (CCAs) in chromosomes 1, 3, and 7 frequently appear in the bone marrow (BM) of patients with FA and are associated with MDS/AML progression. Given the underlying DNA repair defect that characterizes FA, non-clonal chromosomal abnormalities (NCCAs) are expected to be common events in the FA BM; in this study, we investigated the presence and significance of NCCA and CCA in the bone marrow (BM) of patients with FA. Here, we transversally examined the BM karyotypes of 43 non-transplanted patients with FA, 41 with non-clinically detectable hematologic neoplasia and two with diagnosed MDS. We searched for the presence of NCCAs, complex karyotypes (CKs), and CCAs as well as their association with the natural history of the disease, including age, degree of BM failure, and neoplastic transformation. NCCAs were observed in the metaphase spreads of 41/43 FA patients; CKs were observed in 25/43 patients; CCAs were found in 15/43 patients; CCAs involving chromosomes 1, 3 and/or 7 were found in four patients; and other autosomes were found in the remaining 11 patients. Overall, we observed a baseline large karyotypic heterogeneity in the BM of FA patients, demonstrated by the ubiquitous presence of NCCA; such karyotypic heterogeneity precedes the eventual emergence of CKs and selection of cells carrying fitness-improving CCAs. Finally, CCAs involving chromosomes 1, 3 and 7, well-known drivers of hematological malignancy in FA, become established. Overall, we observed that the frequency of NCCAs and CCAs increased with age, even though a significant correlation was not found. These observations fit the model of evolution towards cancer that comprises a first phase of macroevolution represented by NCCAs and karyotypic heterogeneity, followed by the establishment of clones with CCAs, leading to microevolution and cancer. NCCAs are the most frequent chromosomal alterations in the bone marrow of patients with AF and constitute a genome with extensive karyotypic heterogeneity that evolves into clones with more complex genomes and can eventually progress to cancer.