Purpose: To retrospectively determine the cumulative survival rate (CSR) and marginal bone level change (ΔMBL) around novel hybrid design tissue-level (TL) dental implants that support multiple-screw-retained restorations. Materials and Methods: Implant CSRs were analyzed at the implant and patient level using Kaplan-Meier estimates. ΔMBL was measured by comparing the periapical loading and follow-up visit radiographs using an improved standardized digital methodology based on image gray levels. ΔMBL outcomes were subject to linear mixed regression to identify potential risk factors. Results: A total of 301 TL implants in 69 patients with an average age of 62.6 ± 11.7 years (range: 36 to 87 years) at the time of implant placement were considered for the analysis. All 301 implants were successfully restored and loaded. The 54-month CSRs at the implant and patient levels were 98.9% (95% CI: 96.7 to 99.6) and 95.3% (95% CI: 86.1 to 98.5), respectively. ΔMBL after a mean follow-up of 22 ± 10.7 months after loading was 0.00 ± 0.57 mm. None of the implant sites showed marginal bone loss exceeding 1.5 mm. Multivariate regression analysis revealed a significant association between ΔMBL and the loading protocol (P = .027) but not between ΔMBL and age or transgingival height. Conclusions: The high CSRs and stable peri-implant marginal bone levels support the use of recent TL implants, which have a hybrid design inherited from the bone-level implant-abutment connection, as a suitable treatment option for restoring partially or fully edentulous patients with a good mid-term prognosis. These results should be complemented by further prospective studies in a real-world multicenter private practice setup that represents the daily realities of implant treatment.