Objective To compare the de novo prolapse rate in the untreated vaginal compartments following conventional vaginal prolapse repair and tension-free vaginal mesh repair.Design Secondary analysis of a randomised controlled trial.Setting Thirteen centres in the Netherlands.Population Women with recurrent pelvic organ prolapse stage II or higher.Methods Random assignment to either conventional vaginal native tissue repair or vaginal mesh insertion.Main outcome measures Primary outcome: de novo pelvic organ prolapse stage II or higher in the untreated vaginal compartments at 12 months after surgery. Secondary outcomes: de novo pelvic organ prolapse at and beyond the hymen, de novo prolapse beyond the hymen and prolapse domain scores of the Urogenital Distress Inventory.Results At 12 months ten of 59 women (17%) in the conventional group versus 29 of 62 women (47%) in the mesh group were diagnosed with a de novo pelvic organ prolapse stage II or higher in the untreated compartment (P < 0.001, odds ratio 4.3, 95% confidence interval 1.9-10.0). Additional apical support to a mesh-augmented anterior repair significantly reduced the de novo prolapse rate. Women with a de novo prolapse in the mesh-treated group demonstrated significantly higher mean bother scores on the domain genital prolapse of the Urogenital Distress Inventory score (13.1 ± 24.2) compared with those without de novo prolapse (2.9 ± 13.9) (P = 0.03).Conclusion Mesh-augmented prolapse repair in only one vaginal compartment is associated with a higher de novo prolapse rate in the untreated compartments compared with conventional vaginal native tissue repair in women with recurrent pelvic organ prolapse.Keywords De novo prolapse, mesh, surgery, untreated compartment, vaginal.Please cite this paper as: Withagen M, Milani A, de Leeuw J, Vierhout M. Development of de novo prolapse in untreated vaginal compartments after prolapse repair with and without mesh: a secondary analysis of a randomised controlled trial. BJOG 2012;119:354-360.