Objective: The aim of this study was to determine if prophylactic mesh placement is an effective, safe, and cost-effective procedure to prevent parastomal hernia (PSH) formation in the long term. Background: A PSH is the most frequent complication after stoma formation. Prophylactic placement of a mesh has been suggested to prevent PSH, but long-term evidence to support this approach is scarce. Methods: In this multicentre superiority trial patients undergoing the formation of a permanent colostomy were randomly assigned to either retromuscular polypropylene mesh reinforcement or conventional colostomy formation. Primary endpoint was the incidence of a PSH after 5 years. Secondary endpoints were morbidity, mortality, quality of life, and cost-effectiveness. Results: A total of 150 patients were randomly assigned to the mesh group (n = 72) or nonmesh group (n = 78). For the long-term follow-up, 113 patients were analyzed, and 37 patients were lost to follow-up. After a median follow-up of 60 months (interquartile range: 48.6–64.4), 49 patients developed a PSH, 20 (27.8%) in the mesh group and 29 (37.2%) in the nonmesh group (P = 0.22; RD: −9.4%; 95% CI: −24, 5.5). The cost related to the meshing strategy was € 2.239 lower than the nonmesh strategy (95% CI: 491.18, 3985.49), and quality-adjusted life years did not differ significantly between groups (P = 0.959; 95% CI: −0.066, 0.070). Conclusions: Prophylactic mesh placement during the formation of an end-colostomy is a safe procedure but does not reduce the incidence of PSH after 5 years of follow-up. It does, however, delay the onset of PSH without a significant difference in morbidity, mortality, or quality of life, and seems to be cost-effective.