The incidence of non-palpable breast cancer is increasing due to widespread screening and neoadjuvant therapies. Among the available tumor localization techniques, radio-guided occult lesion localization (ROLL) has largely replaced wire-guided localization (WGL). This study aimed to compare ROLL and WGL techniques in terms of the effectiveness of isotopic marking of axillary sentinel lymph nodes and to assess patient perspectives along with surgeon and radiologist preferences. A single-center, prospective randomized study enrolled 110 patients with non-palpable breast lesions (56 ROLL, 54 WGL). Breast type, tumor volume, location, histological and radiological features, and localization/surgical duration were evaluated in the context of sentinel lymph node marking using isotope (Technetium-99m labelled human serum albumin) and blue dye. Statistical analysis was performed with significance set at p<0.05 and strong significance at p<0.01. Both techniques were successful in localizing non-palpable lesions (100%). However, patients reported WGL as more painful. A notable difference was observed in axillary lymph node marking, with subareolar isotope injection (used in WGL) showing better results compared to ROLL. While ROLL provided advantages in terms of patient comfort, and logistical simplicity, WGL was superior for axillary sentinel lymph node marking, particularly in inner quadrant tumors, suggesting WGL may be preferred for these cases.