PRRT with [Y-90-DOTA,Tyr3]octreotide (Y-90-SMT487, OctreoTher) has potential benefit in patients with somatostatin receptor positive tumors. We investigated whether toxicity (tox), mainly renal and red marrow (RM), and effects on tumor size are different when the total radioactivity (RA) is given in 4 equal cycles (4-cy) or in fewer cycles (cy), but with higher activity per cy (Hi-cy). Methods: 60 patients (pts) with neuroendocrine tumors were treated with 1 or more cy of Y-90-SMT487 escalating from 4 x 25 to 4 x 100 mCi/m2 (4-cy, n=34; 32 completed 1, 28 completed 4 cy) or 1 to 3 x 100 to 250 mCi/m2, up to a renal limit of 27 Gy (Hi-cy, n=26). The individual RA for a renal dose of 27 Gy had been determined prior to entry by PET using Y-86-SMT487. All pts received concomitant infusion of amino acids for renal protection. The first dose of RA was 60 ± 27 mCi/m2 (mean ± SD) in the 4-cy group, and 164 ± 41 mCi/m2 in the Hi-cy group (P<0.001). The cumulative RA was 219 ± 108 mCi/m2 (4-cy) and 224 ± 58 mCi/m2 (Hi-cy), similar in both groups, as were other baseline parameters. Results: Overall, 9 pts had transient WHO grade 3 and 1 pt grade 4 RM tox; 1 pt had myelodyplasia after 2 years. During the first cy, nadir platelets (Hi-cy: 111 ± 45 x 10E9/L, 28% ± 29% less than baseline) and nadir leukocytes (Hi-cy: 3.2 ± 1.2 x 10E9/L, 38% ± 27% less than baseline) were lower in the Hi-cy than in the 4-cy group (P<0.01), but differences were NS between groups after full dose. Renal tox included 2 pts with radiation nephropathy (late grade 3) and 2 with suspected radiation nephropathy; no pts required dialysis. Pts with follow-up of >30 months (n=13) showed a mean decrease in calculated creatinine clearance of 10.9 ± 4.1 mL/min, or 13.0 ± 4.9% from baseline. Differences between 4-cy and Hi-cy groups were NS. 5 pts had PR, 7 minor response, and 30 SD. In 12 4-cy pts with measurable tumor shrinkage, the smallest size occurred after 17 ± 11 months; in 10 Hi-cy pts after 13 ± 8 months (NS). Conclusions: PRRT with Y-90-SMT487 after individual dosimetry is well tolerated. Except for reversible early RM tox, we did not observe major differences in tox or efficacy between the 4-cy and Hi-cy groups.