Immediate implant-based breast reconstruction (IIBR) is the most commonly used method in breast reconstruction in the United States. However, postoperative surgical site infections (SSIs) can cause devastating reconstructive failure. This study evaluates the use of perioperative versus extended courses of antibiotic prophylaxis after IIBR for the prevention of SSI. This is a single-institution retrospective study of patients who underwent IIBR between June 2018 and April 2020. Detailed demographic and clinical information was collected. Patients were divided into subgroups based on antibiotic prophylaxis regimen: group 1 consisted of patients who received 24 hours of perioperative antibiotics and group 2 consisted of patients who received ≥7 days of antibiotics. Statistical analyses were conducted using SPSSv26.0 with P ≤ 0.05 considered statistically significant. A total of 169 patients (285 breasts) who underwent IIBR were included. The mean age was 52.4 ± 10.2 years, and the mean body mass index (BMI) was 26.8 ± 5.7 kg/m2. Twenty-five percent of patients (25.6%) underwent nipple-sparing mastectomy, 69.1% skin-sparing mastectomy, and 5.3% total mastectomy. The implant was placed in the prepectoral, subpectoral, and dual planes in 16.7%, 19.2%, and 64.1% cases, respectively. Acellular dermal matrix was used in 78.7% of cases. A total of 42.0% of patients received 24-hour prophylaxis (group 1), and 58.0% of patients received extended prophylaxis (group 2). Twenty-five infections (14.8%) were identified, of which 9 (5.3%) resulted in reconstructive failure. In bivariate analyses, no significant difference was found between groups in rates of infection (P = 0.273), reconstructive failure (P = 0.653), and seroma (P = 0.125). There was a difference in hematoma rates between groups (P = 0.046). Interestingly, in patients who received only perioperative antibiotics, infection rates were significantly higher in those with BMI ≥ 25 (25.6% vs 7.1%, P = 0.050). There was no difference in overweight patients who received extended antibiotics (16.4% vs 7.0%, P = 0.160). Our data demonstrate no statistical difference in infection rates between perioperative and extended antibiotics. This suggests that the efficacies of current prophylaxis regimens are largely similar, with choice of regimen based on surgeon preference and patient-specific considerations. Infection rates in patients who received perioperative prophylaxis and were overweight were significantly higher, suggesting that BMI should be taken into consideration when choosing a prophylaxis regimen.