Does leakage impair the therapeutic effect of radiosynoviorthesis (RSO)? Are there differences in leakage between (169)Erbium and (186)Rhenium? At baseline and at 6 and 12 months after RSO, six clinical parameters were scored. Changes in clinical variables over time were summed to a change composite index (CCI), ranging from 0 (no effect) to 12 (maximal effect). CCI >or= 6 was considered successful treatment. Differences in leakage between responders and non-responders, and between (169)Erbium and (186)Rhenium were examined. Regression analyses were performed to explore whether baseline variables predicted leakage. Both at 6 and 12 months response rates were 25 of 36 (69%). Five of 11 (45%) non-responders showed leakage versus 20 of 25 (80%) responders (P=0.06). Mean leakage to lymph nodes was 0.4+/-0.7% versus 2.4+/-0.8% (P=0.04). Median leakage to liver/spleen was 0% versus 0.3% (P=0.4). Only age at the time of injection correlated significantly with leakage to lymph nodes. The (169)Erbium group showed leakage in 1 of 7 (14%) versus 24 of 30 (80%) for the (186)Rhenium group (P=0.002). Mean leakage to lymph nodes was 0.11+/-0.3% versus 2.1+/-2.8% (P=0.001). Median leakage to liver/spleen was 0% versus 0.5% (P=0.006). Leakage to non-target organs does not impair the clinical effect of RSO. Only age predicted leakage to lymph nodes significantly. Other baseline characteristics did not predict leakage. (169)Erbium shows significantly lower leakage to non-target organs than (186)Rhenium in RSO.