© 2016 The Author(s). Background: Previous studies suggested that pre-operative comorbidity was a risk factor for worse outcomes after TKA. To our knowledge, studies have not examined whether postoperative changes in comorbidity impact pain and function outcomes longitudinally. Our objective was to examine if increasing comorbidity postoperatively is associated with worsening physical function and pain after primary total knee arthroplasty (TKA). Methods: We performed a retrospective chart review of veterans who had completed Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Short Form-36 (SF36) surveys at regular intervals after primary TKA. Comorbidity was assessed using a variety of scales: validated Charlson comorbidity index score, and a novel Arthroplasty Comorbidity Severity Index score (Including medical index, local musculoskeletal index [including lower extremity and spine] and TKA-related index subscales; higher scores are worse ), at multiple time-points post-TKA. We used mixed model linear regression to examine the association of worsening comorbidity post-TKA with change in WOMAC and SF-36 scores in the subsequent follow-up periods, controlling for age, length of follow-up, and repeated observations. Results: The study cohort consisted of 124 patients with a mean age of 71.7 years (range 58.6-89.2, standard deviation (SD) 6.9) followed for a mean of 4.9 years post-operatively (range 1.3-11.4; SD 2.8). We found that post-operative worsening of the Charlson Index score was significantly associated with worsening SF-36 Physical Function (PF) (beta coefficient (ß) = -0.07; p < 0.0001), SF-36 Bodily Pain (BP) (ß = -0.06; p = 0.002), and WOMAC PF subscale (ß = 0.08; p < 0.001; higher scores are worse) scores, in the subsequent periods. Worsening novel medical index subscale scores were significantly associated with worsening SF-36 PF scores (ß = -0.03; p = 0.002), SF-36 BP (ß = -0.04; p < 0.001) and showed a non-significant trend for worse WOMAC PF scores (ß = 0.02; p = 0.11) subsequently. Local musculoskeletal index subscale scores were significantly associated with worsening SF-36 PF (ß = -0.05; p = 0.001), SF-36 BP (ß = -0.04; p = 0.03) and WOMAC PF (ß = 0.06; p = 0.01) subsequently. None of the novel index subscale scores were significantly associated with WOMAC pain scores. TKA complications, as assessed by TKA-related index subscale, were not significantly associated with SF-36 or WOMAC domain scores. Conclusions: Increasing Charlson index as well as novel medical and local musculoskeletal index subscale scores (from novel Arthroplasty Comorbidity Severity Index) post-TKA correlated with subsequent worsening of physical function and pain outcomes post-TKA. Further studies should examine which comorbidity management could have the greatest impact on these outcomes.