Metal-on-metal (MoM) large headed arthroplasties were suggested to decrease failure rates by means of reduced volumetric wear and enhanced implant stability. However, they caused high rates of revisions due to adverse reaction to metal debris, osteolysis, pseudotumor growth, and other issues. The study aims to present the long-term outcomes of MoM arthroplasties on a large cohort of patients, evaluating the impact of head sizes on survival rate. All data were retrieved from the regional joint register (Registro dell’Implantologia Protesica Ortopedica, RIPO, Italy). We include in the study all patient who underwent cementless MoM total hip arthroplasties (THAs) between 2000 and 2020, dividing them in two subgroups according to head size (<36 mm, ≥36 mm). Failures were recorded up to December 31, 2020. Patients lost to follow-up were excluded. A total of 3813 THAs met the inclusion/exclusion criteria. The average follow-up period is 12.4 years (0–21 years). 178/1625 (or 11.0%) small head MoM THAs and 265/2188 large head ones failed by the end of follow up. Large diameter heads reported lower survival rate (p-value < 0.001), with unexpected higher dislocation rate (1.0 vs. 0.4%). Moreover, large head size was found to increases the risk of metallosis (p-value < 0.0001). Gender, patient’s age and the use of modular neck were not correlated with higher failure rates. MoM implants implants do not have the same reliability as other couplings, considering the significantly greater failure/complication rates. However, the knowledge of risks linked to head size is fundamental for establishing the right type of follow-up to the patient and recognize any complications early.