Background While serum interleukin-6 (IL-6) clearly has been established as a marker of physiologic stress, the validity of IL-6 as a reliable measure of the degree of trauma or stress suffered by an individual with total knee replacement (TKA) remains in question. We hypothesized that if serum IL-6 is a marker of surgical stress, then we would observe marked increases in IL-6 levels in sequential bilateral TKA as compared with unilateral TKA. Methods The study design was a single-surgeon prospective case-control pilot study of sequential bilateral TKA cases and unilateral TKA controls to assess changes in serum IL-6 levels preoperatively, during, at wound closure, and up to 48 hours postoperatively. IL-6 levels were analyzed using a one-way mixed models analysis of variance. Results Eleven patients with unilateral and 12 with bilateral TKA comprised the study sample. IL-6 levels at peak (24 hours postoperatively) for the unilateral control group was 12 times higher compared with baseline (4.6 pg/mL compared with 55.0 pg/mL), while the bilateral TKA group saw a 116-fold increase in IL-6 from baseline to peak at 12 hours postoperatively (2.9 pg/mL compared with 335.0 pg/mL). At “peak,” IL-6 was 6.1 times higher for the bilateral group compared with the unilateral group. Conclusions This pilot study supports the notion that sequential bilateral TKA produces a far greater surgical stress, as measured by IL-6. Careful patient selection, counseling, and consideration of staging procedures are advised.