Since the introduction of chlorambucil as a treatment for chronic lymphocytic leukemia (CLL) in the 1960s, several alternative treatment regimens have been explored. We performed a multiple-treatment meta-analysis using direct and indirect data based on all available head-to-head randomized controlled trials (RCTs) to compare the benefits and harms of first-line treatments for untreated advanced-stage CLL. Two reviewers independently identified RCTs comparing overall survival and progression-free survival between two or more first-line treatments. Twenty-five trials involving 7926 patients were included. Of the 25 eligible RCTs, 30 (n=7741 patients) and 12 (n=3910 patients) treatment pairs were included in the multiple-treatment meta-analysis of overall and progression-free survival, respectively. Trials generally enrolled younger and less complicated patients than actual clinical practice. There was no evidence for inconsistency between direct and indirect data. Based on combined direct and indirect data, no single treatment showed significantly better overall survival than any other, and credible intervals were wide. Among six newer treatments with longer progression-free survival compared with chlorambucil, fludarabine-rituximab-based chemoimmunotherapy (HR = 0.24, 95% CrI: 0.13-0.51) and bendamustine (HR = 0.23, 95% CrI: 0.13-0.42) had the largest PFS benefit. Limited data on treatment-related mortality precluded multiple-treatment meta-analysis. In conclusion, published randomized evidence on overall survival is insufficient to recommend any particular first-line treatments. Any progression-free survival differences may be applicable to relatively young uncomplicated patients.