AIM: To compare the safety and effectiveness of eyelid treatment with the ILux®-MGD Treatment System in one session versus five sessions of mechanical meibomian gland expression (MMGE) in patients with moderate to severe meibomian gland dysfunction (MGD). METHODS: A prospective, randomized, open-label, and controlled clinical trial that compared one session of the ILux® MGD Treatment System versus five sessions of MMGE in both eyes of 130 patients aged ≥18y with Ocular Surface Disease Index (OSDI) scores ≥13, total meibomian gland scores (MGS) of <15 in the lower eyelid of each eye, and non-invasive tear break-up time (NI-TBUT) <10s, who were randomized 1:1 to ILux® or MMGE. RESULTS: The mean age was 58±17.49y. Baseline total MGS scores in both treatment groups were comparable. During follow-up, there were significant differences in total MGS and per sector with P<0.001. Multivariate analysis was performed using generalized estimating equations corresponding to the generalized linear model for repeated means to determine the treatment relationship with total MGS, NIBUT, and OSDI. There was a significant difference between ILux® and MMGE (P<0.001) at follow-up from the first to the twelfth month in MGS, NI-BUT, and OSDI scores. No adverse events were reported. CONCLUSION: ILux® treatment compared to MMGE significantly improves symptoms and signs in patients with moderate to severe MGD for one year without adverse events.