Rheumatoid factor (RF) is one of the most characteristic laboratory parameters in rheumatoid arthritis (RA), and its specificity for this disease increases when the titer is high. We investigated the diagnoses associated with high titers of RF and whether they are associated with a poor prognosis of RA. METHODS Patients with RF titers higher than 300 IU/ml were studied (nephelometry) during a three-year period in a general hospital. Patients with RA were compared with other group of patients with RA and RF lower than 300 IU/ml regarding functional capacity, presence of nodules, HLA-DR4 and radiologic status, in a retrospective cohort study. RESULTS RF was quantitated in 2,181 patients and was higher than 300 IU/ml in 79 cases; 63 among patients in this group (80%) had RA, and the remaining patients inflammatory diseases of the connective tissue (four patients), palindromic rheumatism (two), liver disease (two), infection (one) and neoplasm (one). In two cases the diagnosis was arthrosis and in one case arthralgia of unknown origin. RA with RF higher than 300 IU/ml had a higher frequency of rheumatoid nodules than RA with RF lower than 300 IU/ml (p = 0.01; RR: 2.26; 95% CI: 1.18-4.35). The index of functional capacity and rate of HLA-DR4 and erosions was similar in both RA groups. CONCLUSIONS In a patient with a high RF titer, RA should be first ruled out, followed by other inflammatory diseases, collagenosis and liver diseases. The likelihood of finding a healthy patient with arthrosis or soft tissue rheumatism was very low. In RA, rheumatoid nodules were significantly associated with RF with titers higher than 300 IU/ml.