BACKGROUND: Accurate diagnosis of periprosthetic infections following breast reconstructions is paramount to reduce morbidity. Alpha defensin-1 (AD-1) is an antimicrobial peptide released by neutrophils. This study evaluates the relationship between quantitative AD-1 levels and infection severity in patients with suspected periprosthetic infection. METHODS: Retrospective review was conducted of patients with prior breast implant reconstruction undergoing surgery for either suspected infection or prosthesis exchange and revision. The AD-1 level in periprosthetic fluid was sent for quantitative analysis. Association between AD-1 levels with outcomes, management, systemic markers of infection, and overall infection severity was evaluated. RESULTS: Thirty-eight breasts were included. Infected breasts had higher AD-1 levels (3.91 versus 0.14, < 0.01), greater odds of erythema [odds ratio (OR) 2.98 (1.53-5.82), = 0.01], purulence [OR 2.84 (1.51-5.35), = 0.01], fever [OR 1.84 (1.15-2.93), = 0.01], threatened implant exposure [OR 2.97 (1.48-5.95), < 0.01], and true implant exposure [OR 1.79 (1.04-3.08), = 0.04]. Increasing AD-1 was an independent risk factor for washout ( < 0.01), and explant [OR 2.48 (1.47-4.2), < 0.01]. AD-1 positively correlated with white blood cell count (β = 1.81 cells/µL, < 0.01), and serum lactate (β = 0.19 meq/L, < 0.04). Increasing AD-1 level was an independent predictor of infection severity (χ² = 22.77, < 0.01). CONCLUSIONS: AD-1 levels correlate with infection severity, highlighting its potential both when clinical examination is ambiguous and when treatment response is being monitored. Although further evaluation is warranted, AD-1 may demonstrate utility in novel breast implant salvage algorithms.