The aim of our prospective non-randomized clinical study was to analyze operative data, short-term results, safety, efficacy, complications, and prognostic factors for single-level total lumbar disc replacement (TLDR), and to compare results between different levels (L4–L5 vs. L5–S1). Thirty-six patients with single-level L4–L5 or L5–S1 TLDR, with 1-year minimum follow-up (FU), had complete clinical [SF36, visual analog scale (VAS), Oswestry Disability Index (ODI)] and radiological data, and were included in our study. Mean FU was 38.67 ± 17.34 months. Replaced level was L4–L5 in 12 (33.3%) cases, and L5–S1 in 24 cases (66.7%). Mean age at diagnosis was 41.17 ± 7.14 years. 24 (66.7%) were females and 12 (33.3%) were males. Statistical analyses were assessed using t tests or Mann–Whitney test for continuous variables and Chi-square test or Fisher’s exact test analyses for categorical variables. Univariate linear regression and binary logistic regression analyses were utilized to evaluate the relationship between surgical outcomes and covariates (gender, age, etiology, treated level, pre-operative SF36, ODI, and VAS). Mean operative time was 147.03 ± 30.03 min. Mean hospital stay was 9.69 ± 5.39 days, and mean return to ambulation was 4.31 ± 1.17 days. At 1-year FU, patients revealed a statistical significant improvement in VAS pain (P = 0.000), ODI lumbar function (P = 0.000), and SF36 general health status (P = 0.000). Single-level TLDR is a good alternative to fusion for chronic discogenic low back pain refractory to conservative measures. Our study confirmed satisfactory clinical results for monosegmental L4–L5 and L5–S1 disc prosthesis, with no difference between the two different levels for SF36 (P = 0.217), ODI (P = 0.527), and VAS (P = 0.269). However, replacement of the L4–L5 disc is affected by an increased risk of complication (P = 0.000). There were no prognostic factors for intraoperative blood loss or return to ambulation. Age (P = 0.034) was the only prognostic factor for operative time. Hospital stay was affected by level (P = 0.036) and pre-op VAS (P = 0.006), while complications were affected by the level (P = 0.000) and pre-op ODI (P = 0.049). Complete pre-operative assessment (in particular VAS and ODI questionnaires) is important because more debilitating patients will have more hospital stay and higher complications or complaints. Patients had to be informed that complications, possibly severe, are particularly frequent (80.6%).