Formalin-fixed paraffin-embedded (FFPE) tumor biopsy is the current mainstay of genotyping, but is limited by its invasiveness and tumor heterogeneity. Plasma cell-free DNA (cfDNA) constitutes a minimally invasive alternative that may better capture tumor-derived profiles from circulating tumor DNA (ctDNA). This study compares the performance and genomic concordance of cfDNA and FFPE tumor DNA in aggressive non-Hodgkin large B-cell lymphoma.Paired diagnostic FFPE tissue and plasma samples from 15 patients were sequenced with a custom 53-gene panel.Detection thresholds were empirically guided at 1% variant allele frequency (VAF) for cfDNA and 10% for unpaired FFPE DNA. The median number of cfDNA variants was 6 (interquartile range (IQR): 2-11) versus 63 (IQR: 15-250) in FFPE DNA at 1% VAF. Collectively, 102 somatic variants were shared between cfDNA and FFPE DNA with a median of 5 (range: 0-23). cfDNA showed a five-fold lower median VAF for shared variants than FFPE DNA (7% vs. 36%, p  50%. COSMIC database overlap was twice as high for cfDNA compared to FFPE DNA (22% vs. 11%) at 10% VAF.cfDNA has superior specificity for somatic mutation detection but lower sensitivity than FFPE DNA. Modest concordance was demonstrated between the two compartments. Our results support a complementary role of ctDNA in mutational profiling at a 1% VAF threshold in a pragmatic and clinically applicable setup.