Prior studies have outlined C-reactive protein (CRP) within the first 5 d following total hip arthroplasty (THA) as an inappropriate indicator of an early periprosthetic joint infection (PJI). Recently, interleukin-6 (IL-6), as a potential inflammatory marker following total joint arthroplasty (TJA), has gained increasing interest, particularly due to its considerably shorter half-life. The aim of the present study was to assess IL-6 measured on postoperative day 3 following TJA as a prediction marker of early onset PJI. 7,661 patients, who underwent total hip or knee arthroplasty (THA, TKA) at a single institution between 2016 and 2019, were evaluated. Serum IL-6 values were measured on postoperative day 3 and compared between patients, with and without early onset PJI in the postoperative follow-up, matched for age, gender, Surgical Site Infection Risk Score and Charlson comorbidity index. Overall (n = 7,661), there was no statistically significant difference in serum IL-6 levels comparing patients with and without early onset PJI following THA [38.9 pg/ mL vs. 32.0 pg/mL, p = 0.116] and TKA [30.6 pg/mL vs. 28.2 pg/mL, p = 0.718]. Male gender and high body mass index were associated with an increased risk of early onset PJI following THA (p = 0.027, p = 0.002). Matched cohort analysis (n = 86) showed no statistically significant difference in serum IL-6 levels between patients with and without early onset PJI following THA (p = 0.680) and TKA (p = 0.910). Serum IL-6 values on postoperative day 3 following THA or TKA could not predict early onset PJIs.