Rheumatoid nodules are a rare extraarticular manifestation of juvenile rheumatoid arthritis (JRA), usually detected in patients with polyarticular-onset disease and positive rheumatoid factor (RF). To date, there has not been a published report of rheumatoid nodules in systemic-onset JRA. Low-dose methotrexate (MTX) is generally considered to be the most useful second-line drug in the treatment of polyarticular JRA. In adult RA, MTX has been shown to be associated with appearance and progression of rheumatoid nodules. This report describes a 3-year-old girl with RF-negative, antinuclear antibody-negative systemic JRA who developed multiple rheumatoid nodules on the scalp and trunk during MTX therapy. The first nodule developed on the scalp 6 months after MTX treatment was initiated. Previous treatment with azathioprine was not associated with nodulosis. This represents an atypical case of MTX-associated accelerated nodulosis in systemic JRA, and raises the problem of treatment plan modification in the presence of this side effect.