The purpose of this study was to evaluate cases of early aseptic failures presented during the first 5-year follow-up in a group of 981 primary total knee arthroplasty (primary TKA). Predisposing factors as well causes of failures and postoperative complications in different groups of aseptic failures were re-assessed and compared to a control group. A retrospective and cohort study compared one group of 944 primary TKA without surgical revision (890 patients) (Group A) with 22 primary TKA (22 patients) (Group B) that had revision TKA secondary to aseptic failure during the first five years follow-up. The cases of isolated patellar button replacement (n = 8) and infection (n = 7) were not considered in this study. All patients underwent a systematic assessment that included clinical and radiographic examinations, and IKS scores. Aseptic failure was more prevalent at the first 2-year follow-up (63%). TKA loosening (n = 11) and undiagnosed pain (n = 7) were considered the most frequent modes of failures, and laxity (n = 1) was a very rare early cause of failure. The aseptic failure group was characterized as average 5 years younger with a greater number of previous knee surgeries, lower IKS scores improvement, and more postoperative pain compared to control group, despite the fact that the aseptic failure group showed a prevalence of cases during the first 2-year follow-up. Inside this group, the undiagnosed pain group had lower improvement of IKS scores, a remarkable prevalence in prior surgical procedure (71%) and a minor mean interval between primary and revision TKA (11.6 months).