Purpose A novel attachment system for implant-retained overdentures (IRODs) with novel material combinations for improved mechanical resilience and prosthodontic success (Novaloc) has been recently introduced as an alternative to an existing system (Locator). This study investigated whether differences between the Novaloc and Locator attachment systems translate into differences in implant survival, implant success, and patient-centered outcomes when applied in a real-world in-practice comparative setting in patients restored with mandibular IRODs supported by 2 interforaminal implants (2-IRODs). Methods This prospective, intra-subject crossover comparison compared 20 patients who received 2 intra-foraminal bone level tapered implants restored with full acrylic overdentures using either the Locator or Novaloc attachment system. After 6 months of function, the attachment in the corresponding dentures was switched, and the definitive attachment system type was delivered based on the patient's preference after 12 months. For the definitive attachment system, implant survival was evaluated after 24 months. The primary outcomes of this study were oral health-related quality of life and patient preferences related to prosthetic and implant survival. Secondary outcomes included implant survival rate and success, prosthetic survival, perceived general health, and patient satisfaction. Results Patient-centered outcomes and patient preferences between attachment systems were comparable, with relatively high overall patient satisfaction levels for both attachment systems. No difference in the prosthetic survival rate between study groups was detected. The implant survival rate over the follow-up period after 24 months in both groups was 100%. Conclusions The results of this in-practice comparison indicate that both attachment systems represent comparable candidates for the prosthodontic retention of 2-IRODs. Both systems showed high rates of patient satisfaction and implant survival. The influence of material combinations of the retentive system on treatment outcomes between the tested systems remains inconclusive and requires further investigations.