We aimed to investigate the safety of intraperitoneal administration of the combination of fosfomycin, metronidazole, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in patients undergoing appendectomy. We conducted a prospective phase II clinical trial in 14 otherwise healthy men suffering from uncomplicated appendicitis. After appendectomy, the trial treatment was administered intraperitoneally and left in the abdominal cavity. Trial treatment consisted of 4 g fosfomycin, 1 g metronidazole, and 50 µg rhGM-CSF in a total volume of 500 ml. Safety was evaluated through white blood cell count where a toxic effect was predefined. We evaluated harms and adverse events, repeated biochemical markers, vital signs, and length of stay. White blood cell count did not drop below the toxic range. The recorded harms were dizziness, discomfort when breathing deeply, no flatus, and bloating. Adverse events included three patients with diarrhoea after discharge and one patient with a hypotensive episode. No serious adverse events or infectious complications occurred. Intraperitoneal administration of fosfomycin, metronidazole, and rhGM-CSF was safe in otherwise healthy men undergoing laparoscopic appendectomy. There were some possible harms and adverse events but we were unable to assess if they were related to anaesthesia, surgery, or the trial treatment.