OBJECTIVE: To investigate practicability, efficacy and tolerability of low starting doses of Sandimmun (cyclosporin A) (2.5 mg/kg daily) in patients with severe refractory rheumatoid arthritis in the short (6 months) and middle (12 months) term. METHODS: Fifty-nine patients, presenting with active and severe rheumatoid arthritis unresponding to conventional DMRADs were allowed to start Sandimmun at the dose of 2.5 mg/kg daily. This dose was progressively increased by steps of 25 mg daily up to a maximum of 5 mg/kg daily according to the renal function and blood pressure. RESULTS: A mean maintenance dose of 3.9 mg/kg daily was reached after 5 months and maintained throughout the study. Twenty-one patients (36%) completed the one year study. The reasons for discontinuation were: inefficacy (13), adverse events (17), both inefficacy and adverse events (5) and non-compliance (3). For those patients who completed the trial, clinical relevant improvements were observed within 3 months of treatment and were maintained until the end of the study for the Lee functional and the Ritchie articular index, as well as for the number of tender and swollen joints. No changes for the grip strength, the biological and immunological parameters were observed. Mean serum creatinine values rose from 0.81 mg/dl at start to 1.1 mg/dl after 5 months of therapy and remained at that level throughout the study. In patients who discontinued, the serum creatinine level nearly normalized after one month of Sandimmun withdrawal. One hundred and sixty-two side effects were reported of which most were minor and known to occur with Sandimmun. Twenty-two cases (37% of patients) dropped out for adverse events before 1 year treatment. The criteria to withdraw the patients from the study differed greatly from centre to centre. CONCLUSIONS: Managing RA patients presenting with very long and severe disease remains difficult. Therefore low dose Sandimmun (2.5-5 mg/kg daily) appears to be a valuable therapeutic opportunity in RA patients refractory to various other conventional drugs, including methotrexate.