BACKGROUND: Hand sepsis is a common cause of morbidity. The study was conducted in the KwaZulu-Natal province of South Africa, investigating the bacteriological profile and aetiology of hand sepsis, aiming at optimising empiric antibiotic therapy. METHODS: This is a descriptive study of 120 patients who presented to the plastic surgery department of Inkosi Albert Luthuli Central Hospital with hand sepsis, from January 2017 to April 2019, that required surgical drainage. Data recorded included: aetiology of sepsis, underlying comorbidities, length of hospital stay, and outcome. A pus swab was taken during surgical drainage for microscopy, culture and sensitivity (MCS) analysis. The relationship between clinical factors and microbiological findings was analysed. RESULTS: The predominant bacterial strains cultured from infected patients, excluding methicillin-resistant Staphylococcus aureus, were Staphylococcus aureus (80.8%) and Streptococcus spp. (20.0%), mostly due to spontaneous onset infection (58.3%). Cultures of the more problematic Streptococcus spp. were more frequently associated in patients with diabetes mellitus (60.0%), penetrating trauma (41.9%), or blunt trauma (31.3%). The diabetes group in isolation had the longest median hospital stay of 8 (5-15) days, the most need for multiple procedures (60.0%), amputations (30.0%), and skin grafts (20.0%). The most effective antimicrobial drug particularly in mixed cultures was amoxicillin-clavulanic acid. CONCLUSION: Staphylococcus aureus infection was the most common. Streptococcus spp. occurred more frequently in patients with traumatic injury and diabetes mellitus. The latter required further surgical procedures and an increased hospital stay. Amoxicillin-clavulanic acid is the preferred empiric antimicrobial agent.