The optimal duration of postsurgical antibiotic therapy for native hand and finger joint septic arthritis is unknown. We conducted a three-year (May 2015–May 2018), prospective, unblended, single-center, interventional study of adult patients agreeing to a randomization (1–1) to either 2 or 4 weeks of systemic and targeted antibiotic therapy after surgical drainage for native joint infection of the hand or wrist. It was a non-inferiority trial with a lower margin of 10% and two major outcomes—cure of infection and persistent (mechanical) sequelae at the last control visit. We excluded patients with implant-related infections while the implant was still in place, patients without surgical lavage, and patients with short follow-ups (<2 months). We enrolled 85 different episodes among 85 patients for the per-protocol-analysis (median age 48 years, 32 (38%) females, 9 immune-suppressed). The main origins of infection were bites (20 episodes) and the main pathogens were Staphylococcus aureus and Pasteurella multocida (20 and 12 episodes). Overall, 39 patients were treated during 2 weeks of systemic antibiotics, and 46 patients during 4 weeks, of which a median of 1 and 2 days intravenously. The most frequently prescribed oral antibiotic drugs were amoxicillin-clavulanate, levofloxacin or clindamycin. The median number of surgical lavages was 1 in both arms. Recurrence of infection, after stop of antibiotic treatment, was noted in 3 patients (4%)—1 in the 2 weeks’ arm (97% cure) and 2 in the 4 weeks’ arm (96% cure+ Fisher-exact-test, P=0.87). In contrast, the proportion of slight mechanical sequelae were 54% in the short versus 50% in the long arm (P=0.63). However, among them only 5 (13%) and 6 (13%) sequelae needed further surgical or medical interventions (P=0.43). The results fulfilled our base-line non-inferiority requirements. Two weeks of targeted antibiotic therapy for drained septic arthritis in hand surgery was not inferior to four weeks regarding cure of infection or sequelae.