Using [99mTc]pertechnetate as an aqueous space marker, the permeability of liposomes composed of seven different mixtures of distearoylphosphatidylcholine (DSPC) and sphingomyelin (SM) was determined. Liposomes containing 20-33% SM were the least permeable in the presence of rheumatoid synovial fluid. Following injection of 99mTc-containing liposomes into the knee joints of rabbits, retention of 99mTc in the knee was more than 200 times greater than following injection of nonencapsulated [99mTc]pertechnetate. The knee clearance biologic half time of 99mTc with DSPC/SM (4:1) liposomes was 64 h. Most of the activity that had leaked from the knee was not found in extra-articular tissues, suggesting rapid excretion. When DSPC/SM (4:1) liposomes were labeled with 111In(oxine), a knee clearance biologic half time of greater than 1200 h was observed.