Minimal residual disease (MRD) assessment has emerged as an important indicator of therapy efficacy and a surrogate for progression-free survival in chronic lymphocytic leukaemia (CLL) due to the emergence of very effective time-limited combination treatments of targeted medicines. Multicolor flow cytometry, which looks for CLL cells in the bloodstream, is the standard method. In the lymph node, however, appears to be less sensitive for detecting MRD. Serial analyses of circulating tumor DNA (ctDNA) in patients with CLL treated with obinutuzumab, acalabrutinib, and venetoclax in the phase II CLL2-BAAG study to see if a cell-free method may circumvent this constraint. Digital droplet PCR in blood plasma was used to monitor patient-specific variability, diversity, joining (VDJ) rearrangements, and somatic driver mutations before, during, and after treatment. They were also routinely compared to complementary flow cytometry data. There was a significant degree of agreement between ctDNA and flow cytometry in the 381 sample pairs. Despite the fact that uMRD was determined in 152 samples, clone-specific ctDNA was found in 44 of them (29%). (defined as less than one CLL cell in 10,000 normal leukocytes). Flow cytometry revealed MRD more than 10-4 in 29 ctDNA-negative samples. Equally, as well as patient-specific VDJ rearrangements in plasma, somatic driver mutations were also found. Compared to 4-color flow cytometry, ctDNA appeared to better precisely reflect the overall disease burden across compartments in individuals with the primarily nodal residual illness.