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Resistance mutations can be detected in 75% of CLL patients progressing under BTK inhibitor therapy. Using semiquantitative wild-type-blocking (WTB) RT-PCR for BTK and Sanger sequencing for PLCG2 mutations, we compared detection sensitivity of cellular versus circulating tumor DNA (ctDNA) in 20 sample pairs of 13 consecutive patients.With an assay sensitivity of 0.06%, 7 patients had a BTK-C481S and one a PLCG2-G667E mutation. Cellular DNA was positive in 10 but ctDNA only in 6 samples, giving false-negative results in samples with low mutational burden.In summary, WTB-PCR is cost-effective and routinely applicable but misses low frequency mutations when using ctDNA.