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Splenomegaly is frequently found in non-Hodgkin's lymphoma (NHL) patients. This study evaluated the implications of splenic volume change in response to radioimmunotherapy (RIT) using radiolabeled Lym- 1 antibody. Methods: Twenty-nine NHL patients treated with radiolabeled-Lym-1 and 9 breast cancer patients, the reference group, treated with radiolabeled ChL6, BrE-3, or m170, were analyzed using X-ray computer tomography (CT) splenic images obtained before and after RIT. Patient-specific radiation doses to the spleen were determined using actual splenic volume determined by CT and body weight. Results: Of 29 NHL patients, 13 that had splenic volumes equal or less than 310 mL, there was little or no change in splenic volume after RIT, despite splenic radiation doses as high as 23.1 Gy (median 8.0 Gy). Similarly, in a reference group of 9 breast cancer patients, there was little or no change in splenic volume after RIT, despite doses as high as 14.4 Gy (median 11.5 Gy). In the remaining 16 NHL patients, splenic volumes decreased in 13 patients, with initial volumes of 380–1400 mL, by 68–548 mL despite splenic radiation doses as low as 1.1 Gy (median 3.2 Gy); splenic volumes increased in the other 3 patients after RIT. Although not statistically significant in this small series, therapeutic remission, defined conventionally by nodal tumor response, was more likely when splenic volume decreased after RIT. All 10 NHL patients with greater than a 15% decrease in their splenic volumes after RIT had nodal tumor response (5 complete response, 5 partial response). There were 12 responders (5 complete response and 7 partial response) in 19 NHL patients with less than a 15% decrease in splenic volume after RIT. Conclusions: Splenic volume decreased in NHL patients with splenomegaly, despite splenic radiation dose as low as 1.1 Gy. In the absence of splenomegaly, splenic volume did not decrease, even after much higher radiation doses. RIT with radiolabeled-Lym-1 may benefit NHL patients with splenomegaly, with reduction in splenic volume likely owing to a therapeutic effect on malignant lymphocytes.