This study describes the natural history of patients with polycystic liver disease, a rare disorder characterized by multiple hepatic cysts. Cases were identified through review of charts from a hepatology practice, a hepatobiliary surgery practice and a retrospective chart review of inpatient charts from 1990 to 2002. All patients had greater than four simple liver cysts without infectious etiology. Medical records were reviewed for history, physical examination, imaging, and laboratory data. Patients' family practitioners provided follow-up. Fifty-three cases (62.3% female, 37.7% male) were identified. The mean age at diagnosis was 56.4 yr. Thirty-eight cases (71.7%) had associated polycystic kidney disease. The minority of patients were symptomatic at diagnosis (pain in 19 (36.5%), dyspnea in 5 (9.6%), and restricted mobility in 5 (9.6%) with hepatomegaly in 23 (45.1%). Follow-up information was attainable for 40 patients with a mean follow-up duration of 4.69 yr (range 0.1-15 yr). Within this subgroup, 9 patients (22.5%) had cyst bleeding, 5 (12.5%) had cyst rupture, 5 (12.5%) had cyst infection, 12 (30%) required an intervention. One patient (2.5%) developed portal hypertension, and two (5%) received a liver transplant. One patient (2.5%) died due to complications from liver cysts. Most patients in this highly selected cohort were asymptomatic with normal hepatic function. Pain was the most common symptom. The natural history is variable however, with some patients developing complications including portal hypertension. Minimally invasive interventions are appropriate initially, with hepatic resection and liver transplantation reserved for those with severe symptoms or life-threatening complications.