Chronic lymphocytic leukemia (CLL) patients with TP53 mutations experience chemo-refractory disease and are therefore indicated for targeted therapy. However, the significance of low-burden TP53 mutations with <10% variant allele frequency (VAF) remains a matter of debate. Here we describe clonal evolution scenarios of low-burden TP53 mutations and analyzed their clinical impact in a "real-world" CLL cohort. TP53 status was assessed by targeted NGS in 511 patients entering first-line treatment with chemo/immunotherapy and 159 relapsed patients treated with targeted agents. Within the pre-therapy cohort, 16% of patients carried low-burden TP53 mutations (0.1-10% VAF). While their presence did not significantly shorten event-free survival after first-line therapy, it affected overall survival (OS). For a subgroup with TP53 mutations of 1-10% VAF, the impact on OS was only observed in patients with unmutated IGHV that had not received targeted therapy, as patients benefited from switching to targeted agents regardless of initial TP53 mutational status. Analysis of the clonal evolution of low-burden TP53 mutations showed that the highest expansion rates were associated with FCR in both first and second-line treatment (median VAF increase 14.8x and 11.8x, respectively) in contrast to treatment with less intense chemo/immunotherapy regimens (1.6x) and without treatment (0.8x). In the relapsed cohort, 33% of patients carried low-burden TP53 mutations, which did not expand significantly upon targeted treatment (median VAF change 1x). Sporadic cases of TP53-mut clonal shifts were connected with the development of resistance-associated mutations. Altogether, our data support the incorporation of low-burden TP53 variants in clinical decision-making.