The effect of high altitude, long-term hypoxaemia on placentome morphology in the sheep was examined using singleton and twin pregnant ewes. Normoxic twins had lower fetal and placental weights (3.7 ± 0.2 kg and 215 ± 26 g, respectively) than normoxic singleton fetuses (4.3 ± 0.2 kg and 336 ± 17 g, respectively). Fetal and placental weights were similar in normoxic singleton and high altitude (3820 m) hypoxic singleton fetuses (4.3 ± 0.2 and 4.4 ± 0.4 kg, 336 ± 17 and 342 ± 62 g, respectively). The distribution of placentome types was classified into four major categories (A-D) and for normoxic singletons was as follows: A=76 ± 4, B=22 ± 3, C=1 ± 2, and D=1 ± 1. Normoxic twins tended to have more type B (type A=63 ± 10, B=33 ± 8, C=2 ± 1, and D=2 ± 1). High altitude hypoxic singletons had significantly fewer type A (33 ± 4) and more type B (50 ± 3), C (10 ± 7), D (7 ± 1) placentomes than normoxic singletons. In addition, in the sea-level control group, five animals were found to be spontaneously hypoxic with a placentome distribution similar to that of the high altitude hypoxic fetuses. In conclusion, both high altitude, long-term hypoxia and low altitude spontaneous hypoxia lead to a significant change in placentome distribution with less type A and increases in types B, C and D. Physiologically, the change in the several placentome types with high altitude hypoxia suggests an acclimatization response to optimize transplacental exchange efficiency.