Although there are numerous studies about routine histopathological analysis during arthroplasty surgeries, most of them showed that new diagnoses have rarely been obtained as a result. The aim of this study was to evaluate the efficacy of routine pathological analyses of synovia resected during primary total knee arthroplasty in patients with osteoarthritis and its relevance in the treatment process. Of the 47 included patients who were followed up prospectively, 26 patients had clinical and histopathological concordant diagnoses and 21 patients had discrepant diagnoses. Oxford knee score and visual analogue score were performed for all the patients. Kallgren-Lawrence score was used for radiological analyses. The Mann-Whitney U test was used to examine the differences between the abnormally distributed variables. Mean age was 65.9 ± 4.3 years (range, 50–89 years) and mean follow-up time was 19 ± 7.8 months (range, 6–39 months). Grade IV gonarthrosis was found to be statistically lower in the discrepant group (p = 0.046). The mean preoperative Oxford knee score was 16.8 ± 2.3 (range, 2–23) and the mean postoperative Oxford knee score was 44.6 ± 1.8 (range, 27–48; p = 0.016). Postoperative Oxford knee scores and VAS were significantly increased in both the concordant and discrepant groups (p = 0.026 and p = 0.035, p = 0.019 and p = 0.039, respectively). Resection and histopathologic analyses of the hypertrophied and inflamed synovium encountered during primary arthroplasty procedure should be performed. This examination not only could provide crucial information that may influence the postoperative follow-up guidelines but also could help us to expand our knowledge and awareness of rare diseases that might yield osteoarthritis. The level of evidence for the study is level II.