Patients with cystic fibrosis who have totally implantable venous access devices often have other consequences of their multi-system disease which predispose them to catheter-associated systemic infection. We describe four episodes of fungaemia in three patients. Each case presented with persistent fever during an acute respiratory exacerbation. The four episodes were successfully treated, but removal of the venous access device was necessary in each case. Identified risk factors for systemic fungal injection were: combinations of a severe background respiratory deficiency; an acute respiratory exacerbation; malnutrition; repeated and frequent broad spectrum antibiotic therapy; parenteral nutrition; and diabetes mellitus. Unexplained fever in high risk patients with cystic fibrosis who have indwelling venous access systems should be treated empirically with antifungal agents while awaiting blood culture results. If fungaemia is confirmed the venous access device must be removed. Daily prophylactic fluconazole may prevent recurrences.