<p>Several recent trials of new chronic lymphocytic leukemia (CLL) therapies used results of measurable residual disease (MRD)-testing as a primary endpoint assuming it is an accurate surrogate for progression-free survival (PFS) which is, itself, a surrogate endpoint for survival. But whether MRD-testing results accurately correlates with PFS following Bruton tyrosine kinase-inhibitor (BTK-i) therapy with or without venetoclax or for fixed duration therapy regimens is controversial. We searched PubMed, Web of Science, Embase, and Cochrane Library up to February 8, 2025, identifying 43 trials involving 9628 subjects to assess MRD’s accuracy in predicting PFS. At the individual-level subjects with detectable MRD (dMRD) had a significantly higher risk of progression or death than those with undetectable MRD (uMRD; Hazard Ratio [HR] = 3.67; 95% Credibility Interval [CrI] 3.34, 4.03; <i>P</i> &lt; 0.01). In contrast, MRD-testing results and PFS were weak at the trial-level (Spearman rho [<i>R</i>] = -0.33; Determination Coefficients [<i>R²</i> ] = 0.06), especially for BTKi- therapy (<i>R</i> = –0.05, <i>R²</i> = 0.03) and venetoclax-based therapies (<i>R</i> = –0.28, <i>R²</i> = 0.02). Correlations were stronger for therapies involving drugs such as chemoimmunotherapy and/or monoclonal antibodies, where MRD tests of bone marrow (<i>R</i> = –0.94; <i>R</i>^<i>2</i> = 0.86) were more accurately predicted PFS than blood. In sensitivity analyses stratified by treatment approach we found a correlation of treatment-effect in fixed-duration therapy approaching the pre-specified validity threshold (<i>R</i> = –0.80 [–0.93, –0.53]; <i>R²</i> = 0.43, <i>P</i> &lt; 0.01). Our data indicate the accuracy of MRD-testing results to surrogate PFS is context-dependent, influenced by treatment approach, therapy type, and the sampling source, and should be interpreted cautiously when informing clinical or regulatory decisions.</p>