C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) play helpful roles in determining the presence of infection after TKA. To provide baseline values, we documented normative temporal values of CRP and ESR in unilateral and staged bilateral TKAs for osteoarthritis. Levels of CRP and ESR were evaluated before surgery and on the first, second, fifth, seventh, fourteenth, forty-second, and ninetieth postoperative days in 320 uncomplicated primary TKAs. C-reactive protein and ESR levels were compared in three groups: unilateral (108 knees), first knee bilateral (106 knees), and second knee bilateral (106 knees) groups. All three groups exhibited similar temporal patterns. Mean CRP levels increased rapidly, reaching a peak on the second day and decreased to less than the normal reference level on the forty-second day. They returned to preoperative levels on the ninetieth day. Mean ESR levels peaked on the fifth day and returned close to the preoperative levels only on the ninetieth day. Wide variations were observed and many cases (43%) did not follow the typical patterns. C-reactive protein had greater fold changes, less frequent atypical temporal patterns, and lower correlation between preoperative and postoperative levels than ESR. Our findings should help surgeons interpret CRP and ESR to determine the presence of infection after TKA. LEVEL OF EVIDENCE: Level I, diagnostic study.