Background: Whipple's disease is a rare infectious systemic condition caused by Tropheryma whipplei which, can involve several organs such as the gastrointestinal tract, joins, skin, central nervous system, and eyes. Because of its non-specific symptoms and frequent join involvement preceding other Whipple's disease symptoms, a relevant percentage of patients are treated as inflammatory arthritis and received immunosuppressive treatment such as tumor necrosis factor α inhibitors, associated with Immune Reconstitution Inflammatory Syndrome (IRIS), complicating antibiotic therapy. Case presentation: A 53-year-old male presented with bilateral knee arthritis, a weight loss of 30 kg in 6 months without diarrhea, a chronic febricula at 38°C, and cognitive disorders. He was under treatment with tumor necrosis factor α for a misdiagnosis of presumed post-viral spondyloarthritis. Given the unusual clinical presentation for spondyloarthritis, further tests were performed as Polymerase Chain Reaction (PCR) in blood, saliva, stools, joint fluid of the left knee, and cerebrospinal fluid and revealing the presence of the T. whipplei genome, confirming the diagnosis of WD and antibiotic treatment was started. In addition, an ophthalmic examination revealed that the patient presented bilateral posterior uveitis and an aqueous humor sample confirmed the presence of T.whippley. Thus, the patient was treated with classical Whipple’s disease therapy and subconjunctival corticosteroid injections. At three months, he presented persistent ocular posterior segment inflammation, leading to repeated PCR tests in blood, saliva, cerebrospinal fluid, stools, and aqueous humor, which were negatives. Therefore, an ocular IRIS was considered in the context of posterior uveitis recurrence after the effectiveness of antibiotic therapy and negative samples. Thus, the patient was treated with systemic corticosteroid therapy, allowing ocular inflammatory signs to disappear in both eyes. Conclusions: This case revealed the existence of IRIS-induced uveitis complicating Whipple’s disease. Therefore, ophthalmologists, rheumatologists, and internists should be aware of this rare complication, particularly in the context of previous immunosuppressive therapy.