The red blood cell (RBC) uptake of rubidium-86 (Rb-86), a sensitive in vitro test of RBC membrane transport, was measured in 22 controls, 8 patients with benign breast lesions, and 30 stage I/II, 13 stage III/IV untreated breast cancers. Total Rb-86 transport was measured. Following ouabain block, passive transport was determined, allowing calculation of active Rb-86 uptake by difference. There was a significant decrease in total and passive uptake by RBCs from patients with breast cancer when compared to controls and those with benign lesions (total uptake 58.6 +/- 6.1% versus 63.6 +/- 3.9%, P less than 0.01; passive uptake 38.7 +/- 6.8% versus 42.7 +/- 4.6%, P less than 0.02). The Rb-86 uptake returned towards normal in successfully treated stages-II-to-IV patients. There were no correlations with the patient's age, hematocrit, or incubation hematocrit with RBC Rb-86 uptakes. Results from incubation in Krebs-Ringer solution were not consistent with a plasma blocking factor. The RBC potassium content was slightly increased in the cancer patients. This, along with decreased passive transport, eliminates the nonspecific malfunction of the Na-K-pump as an explanation, and suggests that the decreased uptake is a cancer-related phenomenon.