Background <p>Sentinel lymph node biopsy (SLNB) is routinely performed at the time of mastectomy for noninvasive breast disease owing to the potential upgrade on final pathology, resulting in 80% of patients receiving unnecessary SLNB. Superparamagnetic iron oxide nanoparticles (SPIO) are a tracer with extended lymph node marking, facilitating delayed node retrieval in the event of an invasive upgrade. This study assesses the utilization and efficacy of SPIO for potential delayed SLNB for patients undergoing mastectomy.</p> Patients and Methods <p>A retrospective cohort study identified SPIO use from September 2019 to August 2023. Two-sample <i>t</i>-tests, chi squared, and ANOVA were performed to compare indication, clinicopathology, and surgery details among those with or without SPIO injection in patients undergoing mastectomy for ductal carcinoma in situ (DCIS).</p> Results <p>A total of 77 patients received SPIO injection: 33 (42.9%) for potential delayed SLNB and 44 (57.1%) for same-day SLNB. Indications for SPIO use for delaying SLNB were DCIS (23; 69.7%), abnormal imaging (5; 15.2%), high-risk lesions (3; 9.1%), and breast cancer gene (<i>BRCA</i>) mutation (2; 6.1%). A total of 9 out of 33 (27.3%) patients experienced an upgrade and underwent SLNB at a mean of 20 days (range 11–27) after mastectomy, with no differences in the number of nodes removed (2 versus 2.51 nodes; <i>p</i> = 0.61). Of patients undergoing mastectomy for DCIS, 23 (29.5%) received SPIO, while 54 (70.1%) underwent immediate SLNB. Deep inferior epigastric perforator flap reconstruction (<i>p</i> = 0.0021) and necrosis on core needle biopsy (<i>p</i> = 0.00014) were associated with immediate SLNB.</p> Conclusions <p>When utilized at the time of mastectomy for noninvasive disease, most patients receiving SPIO were spared unnecessary axillary surgery and the associated morbidities.</p>