<p>Non-palpable breast cancers require precise localization techniques for surgical excision. Wire-guided localization (WGL) has been the standard, but newer methods like Radioguided Occult Lesion Localization (ROLL) and Radioactive Seed Localization (RSL) offer potential benefits. This study compares the efficacy and safety of these techniques in breast-conserving surgery. A systematic review and meta-analysis of randomized controlled trials (RCTs) compared ROLL, RSL, and WGL in patients undergoing breast-conserving surgery for non-palpable breast cancer. Primary outcomes included surgical margin status, re-excision rates, and operative time. Secondary outcomes were patient satisfaction and adverse events. From 8,300 articles, 2,081 were screened, and 15 RCTs were included. Seven studies compared WGL vs. ROLL (1,441 patients), and eight compared WGL vs. RSL (2,376 patients). RSL associated with a modest reduction compared with WGL for positive surgical margins (RR: 0.71, 95% CI: 0.52–0.98, I² = 42%) and reoperations (RR: 0.71, 95% CI: 0.54–0.95, I² = 0%), both statistically significant. ROLL showed a modest advantage over WGL (RR: 0.66, 95% CI: 0.45–0.96, I² = 0%). Other comparisons, including complications related to marker implantation and sentinel lymph node identification failures, showed no significant differences. Across analyses, effect sizes were small, and heterogeneity among included studies was moderate. RSL and ROLL appear to offer modest advantages over WGL for localizing non-palpable breast cancers in breast-conserving surgery. Both techniques demonstrated favorable outcomes in margin clearance and re-excision rates, though overall differences remain limited. Further research directly comparing ROLL and RSL is needed.</p>