PURPOSE: To examine variations in retinal electrophysiology assessed by multifocal electroretinogram (mfERG) during acclimatization of native highlanders to normobaric normoxia at sea level. METHODS: Eight healthy residents of the greater La Paz area in Bolivia (3600 m above sea level) were examined over 72 days after arriving in Copenhagen, Denmark (sea level). A control group of eight healthy lowlanders was used for comparison. RESULTS: During the period of observation, hemoglobin decreased from 16.7 to 15.0 g/dL (P = 0.0031), erythrocytes decreased from 5.3 to 4.6 trillion cells/L (P = 0.0006), and hematocrit decreased from 49.4% to 42.2% (P = 0.0008). At baseline, day 2 after arrival, the amplitudes (N1, P1, and N2) of the mfERG were 43.1% to 59.9% higher in the highlanders than in the lowlanders (P < 0.017). During acclimatization, the mfERG amplitudes increased 16.9% to 20.4% (P < 0.028) to a level of 73.2% to 87.0% higher in the highlanders than in the lowlanders (P < 0.0008). The increase in numerical amplitudes was proportional to the decrease in erythrocyte concentration (P = 0.023, 0.053, and 0.12 for N1, P1, and N2, respectively). CONCLUSIONS: On arrival at sea level, the highlanders had markedly supernormal multifocal electroretinographic amplitudes that continued to increase during the 72-day period of observation where the highlanders' hematocrit normalized. The results suggest that acclimatization after a change in altitude and hence in ambient oxygen tension involves intrinsic retinal mechanisms and that acclimatization was not complete by the end of the study.