Abstract Purpose Trocar site incisional hernia (TSIH) is a common complication of laparoscopic surgery. In the scientific literature there are few descriptions of methods or tools for its prevention. The aim of this report was to assess the effectiveness and safety of a prophylactic measure designed to lower rates of TSIH. Methods A multicenter randomized double-blinded clinical trial was performed in high-risk patients (diabetes mellitus and/or age ≥ 70 years and/or BMI ≥ 30 kg/m2 and/or extended incision for specimen retrieval) who underwent either elective or emergency laparoscopic cholecystectomy. Patients were assigned to prophylactic onlay polypropylene mesh fixation (intervention) or to standard trocar closure (control). The main aim was to analyze the efficacy of the intervention, taking occurrence of TSIH as the primary outcome. Clinical and radiological follow up lasted at least one year after surgery. Secondary endpoints were technique-related complications (surgical site occurrences). Results One hundred and forty-three patients were randomized and finally 116 were analyzed (64 in the intervention arm and 52 in the control arm). Groups were homogeneous. Mean [SD] age, 65 [18] years; 86 (60.6%) were women. The cumulative TSIH incidence was lower in the intervention group although the differences did not reach statistical significance, assessed either radiologically (16 [25.4%] vs 17 [31.5%], p = 0.538) or clinically (9 [16.1%] vs 9 [20], p = 0.613). No differences in surgical site infection, hematoma or seroma were detected. Mean follow-up was 670 days (range 223–1294). Conclusion Our results show that, when properly assessed, the overall TSIH incidence is extremely high. Although polypropylene onlay mesh placement is safe, it does not appear to be effective in reducing the TSIH incidence rate. Radiological evaluation may be more accurate. Trial registration ClinicalTrials.org NCT03495557. Date of registration: April 12, 2018