Background: Periprosthetic joint infection is one of the devastating complications after primary total knee arthroplasty, which increases the financial burden on patients and affects their quality of life as well. The financial burden of periprosthetic joint infection after joint replacement in developed countries is well known. There is a need to evaluate the economic burden in developing countries such as Pakistan. Methods: This is a single-center, retrospective, case-control study conducted at the Department of Orthopedic Surgery, Liaquat National Hospital Karachi. Cases of primary total knee arthroplasty performed during this study were divided into 2 groups: uneventful primary total knee arthroplasty and periprosthetic joint infection treated with 2-stage revision. To calculate the final cost, we divided the total hospital cost into the hospital stay cost and operating room cost. Results: During study period, 32 patients were diagnosed with periprosthetic joint infection. The total cost of revision surgery for periprosthetic joint infection considering 2 hospitalizations was 1,780,222 ± 313,686 Pakistani rupee (PKR). The total cost of uneventful arthroplasty was 390,172 ± 51,460 PKR. We observed significant difference with respect to economic details between the 2 groups. Conclusions Management of periprosthetic joint infection was 4.5 times more expensive than uneventful primary total knee arthroplasty. Measures should be undertaken to reduce the prevalence of periprosthetic joint infection, thereby reducing patients’ economic burden.