Background <p>Despite the widespread success of total joint arthroplasty (TJA), the impact of chronic immunosuppressant therapy on TJA outcomes remains unclear. This study aimed to evaluate the heterogeneous effects of various immunosuppressants on major postoperative complications in patients undergoing TJA.</p> Methods <p>We conducted a retrospective cohort study using the 2022 National Surgical Quality Improvement Program, which included 114,498 patients with TJA. Patients were categorized based on immunosuppressant use, including anti-rejection drugs, biological disease-modifying antirheumatic drugs (DMARDs), corticosteroids, synthetic DMARDs, and combination therapies. Major postoperative complications, such as cerebrovascular accident, cardiac arrest, myocardial infarction, septic shock, sepsis, pulmonary embolism, deep vein thrombosis, organ/deep space surgical site infection, return to the operating room, and readmission, were treated as a composite variable. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated using multivariable logistic regression to assess the risk of major complications associated with each immunosuppressant category compared to non-immunosuppressant users.</p> Results <p>Of 114,498 TJA patients, 5,018 (4.4%) were receiving chronic immunosuppressant therapy. The incidence of major complications was higher among immunosuppressant users compared with non-users (10.44% vs 6.37%). Multivariable analysis revealed significantly increased risks of major postoperative complications for patients on immunosuppressants, with the highest risks observed in those on anti-rejection therapy (aOR: 1.96, 95% CI 1.29–2.98, <i>p</i> = 0.002), combination therapies (aOR: 1.83, 95% CI 1.45–2.3, <i>p</i> &lt; 0.001), and corticosteroids (aOR: 1.58, 95% CI 1.28–1.96, <i>p</i> &lt; 0.001).</p> Conclusion <p>This study provides the first comprehensive national-level analysis of class-specific immunosuppressant effects on TJA outcomes. Our study revealed that chronic immunosuppressant use significantly increased odds of major postoperative complications in TJA patients, with the highest risks associated with anti-rejection therapies, combination therapies, and corticosteroids. These findings underscore the need for optimized perioperative risk stratification, and tailored management strategies to mitigate adverse outcomes in TJA patients on chronic immunosuppressant therapy.</p> <p><i>Level of evidence III</i>: Retrospective Cohort Study.</p>