Although a variety of biomechanical laboratory investigations and radiological studies have highlighted the potential problems associated with total lumbar disc replacement (TDR), no previous study has performed a systematic clinical failure analysis. The aim of this study was to identify the post-operative pain sources, establish the incidence of post-operative pain patterns and investigate the effect on post-operative outcome with the help of fluoroscopically guided spine infiltrations in patients from an ongoing prospective study with ProDisc II. Patients who reported unsatisfactory results at any of the FU-examinations received fluoroscopically guided spine infiltrations as part of a semi-invasive diagnostic and conservative treatment program. Pain sources were identified in patients with reproducible (> or =2x) significant (50-75%) or highly significant (75-100%) pain relief. Results were correlated with outcome parameters visual analogue scale (VAS), Oswestry disability index (ODI) and the subjective patient satisfaction rate. From a total of 175 operated patients with a mean follow-up (FU) of 29.3 months (range 12.2-74.9 months), n = 342 infiltrations were performed in n = 58 patients (33.1%) overall. Facet joint pain, predominantly at the index level (86.4%), was identified in n = 22 patients (12.6%). The sacroiliac joint was a similarly frequent cause of post-operative pain (n = 21, 12.0%). Pain from both structures influenced all outcome parameters negatively (P < 0.05). Patients with an early onset of pain (< or =6 months) were 2-5x higher at risk of developing persisting complaints and unsatisfactory outcome at later FU-stages in comparison to the entire study cohort (P < 0.05). The level of TDR significantly influenced post-operative outcome. Best results were achieved for the TDRs above the lumbosacral junction at L4/5 (incidence of posterior joint pain 14.8%). Inferior outcome and a significantly higher incidence of posterior joint pain were observed for TDR at L5/S1 (21.6%) and bisegmental TDR at L4/5/S1 (33.3%), respectively. Lumbar facet and/or ISJ-pain are a frequent and currently underestimated source of post-operative pain and the most common reasons for unsatisfactory results following TDR. Further failure-analysis studies are required and adequate salvage treatment options need to be established with respect to the underlying pathology of post-operative pain. The question as to whether or not TDR will reduce the incidence of posterior joint pain, which has been previously attributed to lumbar fusion procedures, remains unanswered. Additional studies will have to investigate whether TDR compromises the index-segment in an attempt to avoid adjacent segment degeneration.