Purpose: The aim of this preliminary clinical report was to evaluate and compare the clinical outcomes of immediate and early loaded mini-implants (MIs) supporting mandibular overdentures. Materials and Methods: Thirty-six completely edentulous patients (20 men and 16 women) complaining of insufficient retention of their mandibular dentures were randomly assigned to two groups. Each patient received four MIs in the interforaminal area of the mandible using the nonsubmerged flapless surgical approach. In group 1 (G1), MIs were loaded with mandibular overdentures using the immediate loading protocol, while in group 2 (G2), MIs were loaded with overdentures using the early loading protocol. The cumulative survival rate was calculated using Kaplan-Meier analysis. Peri-implant health indices (Plaque Index/Bleeding Index), probing depths, and marginal bone levels were recorded for both groups after MI insertions and 6, 12, 24, and 36 months thereafter. Results: The cumulative implant survival rates were 91.7% and 96.7% for G1 and G2, respectively. G1 recorded significantly higher Plaque Index, Bleeding Index, and probing depths than G2 after 12 months, while other observation times demonstrated no significant difference between groups. Most of the recorded marginal bone loss occurred in the first year, and no significant bone loss was noted in subsequent years. After 6 months, marginal bone loss was significantly higher in G1 compared to G2, but no significant differences between groups were noted thereafter. Conclusions: Within the limitations of this study's research design and duration of follow-up outcome analyses, immediate and early loading protocols showed good clinical results with favorable peri-implant tissue response 3 years after implant insertion. Early loading of MIs supporting a mandibular overdenture appears to be preferable to immediate loading.