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A 4-year-old, intact male guinea pig was presented for evaluation of ocular pain and forelimb lameness. Initial examination confirmed that the ocular pain was associated with bilateral anterior uveitis and that the lameness was attributed to a bilateral carpal and metacarpal polyarthropathy. Carpal joint taps revealed nonseptic marked mixed inflammation later confirmed as a nonerosive immune-mediated polyarthropathy. Treatment with topical steroid ophthalmic ointment resulted in rapid resolution of the uveitis; the arthropathy was initially managed with pain medication and anti-inflammatories, then later with doxycycline and cyclosporine. Over the course of 7 days, the joint swelling and pain improved slightly, but the patient developed severe exophthalmos of the right eye. An ocular ultrasound examination revealed a space occupying mass in the retrobulbar space and results of a fine needle aspirate of the mass was diagnosed as lymphoma. Treatment with prednisone was set to be initiated after a 3-day wash-out period of meloxicam, but the patient was euthanized before the initiation of chemotherapy. Necropsy results confirmed the lymphoma had infiltrated the right eye, kidneys, adrenal glands, thyroid glands, lungs, liver, spleen, testicular interstitium, urinary bladder, pancreas, mesentery, lymph nodes, and meninges. This is an unusual presentation of apparent paraneoplastic uveitis and immune-mediated polyarthropathy in a guinea pig.