<i>Background:</i> In this study we hypothesised that proliferation, and the increased expression of G₁-phase cyclins (D1, E) and phosphorylated retinoblastoma protein (p-Rb) is restricted to the early period of synchronized cyst growth in autosomal-recessive polycystic kidney disease (ARPKD). <i>Methods:</i> Lewis polycystic kidney disease <i>(lpk)</i> rats (model of ARPKD; postnatal weeks 1, 3, 6, 12 and 24; n = 6 each) as well as human juvenile cystic renal disease tissue (n = 2) were examined. <i>Results:</i> Between weeks 1 and 3, the percentage cyst area increased 6-fold in <i>lpk </i>rats, followed by a more progressive rise (1.5-fold increase) until week 24. The number of Ki-67-, cyclin D1- and p-Rb-positive cells increased in <i>lpk</i> rats and peaked at week 3, declining thereafter. By serial sections, cysts co-expressed Ki-67, cyclin D1 and p-Rb. The expression of cyclin E was variable, and peaked at week 24. In human tissue, small cysts had a higher expression of p-Rb. <i>Conclusion:</i> Proliferation and the increased nuclear expression of cyclin D1 and p-Rb coincide with the early phase of cyst growth in rats and humans, suggesting that there might be a therapeutic window in which cyclin-dependent kinase inhibitors are most effective in preventing kidney enlargement in ARPKD.