Rabbits (Oryctolagus cuniculus) are a popular companion animal, food animal, and animal model of human disease. Abnormal red cell shapes (poikilocytes) have been observed in rabbits, but their significance is unknown. The objective of this study was to investigate the prevalence and type of poikilocytosis in pet rabbits and its association with physiologic factors, clinical disease, and laboratory abnormalities. We retrospectively analyzed blood smears from 482 rabbits presented to the University of California-Davis Veterinary Medical Teaching Hospital from 1990 to 2010. Number and type of poikilocytes per 2000 red blood cells (RBCs) were counted and expressed as a percentage. Acanthocytes (>3% of RBCs) were found in 150/482 (31%) rabbits and echinocytes (>3% of RBCs) were found in 127/482 (27%) of rabbits, both healthy and diseased. Thirty-three of 482 (7%) rabbits had >30% acanthocytes and echinocytes combined. Mild to moderate (>0.5% of RBCs) fragmented red cells (schistocytes, microcytes, keratocytes, spherocytes) were found in 25/403 (6%) diseased and 0/79 (0%) healthy rabbits (P = 0.0240). Fragmentation and acanthocytosis were more severe in rabbits with inflammatory disease and malignant neoplasia compared with healthy rabbits (P<0.01). The % fragmented cells correlated with % polychromasia, RDW, and heterophil, monocyte, globulins, and fibrinogen concentrations (P<0.05). Echinocytosis was significantly associated with renal failure, azotemia, and acid-base/electrolyte abnormalities (P<0.05). Serum cholesterol concentration correlated significantly with % acanthocytes (P<0.0001), % echinocytes (P = 0.0069), and % fragmented cells (P = 0.0109), but correlations were weak (Spearman ρ <0.02). These findings provide important insights into underlying pathophysiologic mechanisms that appear to affect the prevalence and type of naturally-occurring poikilocytosis in rabbits. Our findings support the need to carefully document poikilocytes in research investigations and in clinical diagnosis and to determine their diagnostic and prognostic value.