Periprosthetic joint infection (PJI) remains one of the most challenging complications of arthroplasty. Optimal antibiotic strategies and the role of multidisciplinary teams (MDT) are not fully defined. We retrospectively analyzed 86 PJI surgical procedures performed between 2017 and 2023 at a tertiary referral center. Clinical data, microbiology, surgical strategy (debridement, antibiotics, and implant retention -DAIR, one-stage, two-stage) and antibiotic regimens were collected. Outcomes were compared across antibiotic classes and treatment teams: orthopaedics alone, orthopaedics with MDT input, and a dedicated MDT (GRIP). Success was defined as infection-free survival without further surgery. Median patient age was 70 years, with high comorbidity and predominance of Gram-positive, monomicrobial infections. Rifampicin-based regimens were associated with higher cure rates than non-anti-biofilm therapy (OR 4.9, 95% CI 1.4–17.8). Flucloxacillin plus rifampicin achieved outcomes comparable to rifampicin–fluoroquinolone combinations. The strongest predictor of success was MDT involvement: in DAIR procedures, cure reached 100% with MDT versus 48% with orthopaedics alone (p = 0.025). Outcomes were similar between teams in one- and two-stage revisions. In this cohort, rifampicin-based therapy improved outcomes in staphylococcal PJI, and flucloxacillin was a valid alternative partner drug. Crucially, MDT management—particularly in DAIR—was associated with superior results. These findings highlight the value of structured multidisciplinary PJI care pathways alongside optimised antibiotic strategies.