A 26-year-old man complained of a sudden decrease in vision in the left eye. He had a past medical history of pauciarticular juvenile rheumatoid arthritis with a positive HLA-B27 haplotype and negative antinuclear antibodies and later development of ankylosing spondylitis. His ocular history was unremarkable. An ophthalmic examination revealed a predominant diffuse vitritis (3+) in the left eye. The uveitis improved after treatment with topical and systemic steroids. Following an extensive clinical and laboratory evaluation, a final diagnosis of HLA-B27-associated uveitis was made. Although uncommon, diffuse vitritis can occur in the setting of this uveitis and may be a predominant symptom.