More prehistoric trepanned crania have been found in Peru than any other location worldwide. We examine trepanation practices and outcomes in Peru over nearly 2000 years from 400 BC to provide a perspective on the procedure with comparison with procedures/outcomes of other ancient, medieval, and American Civil War cranial surgery. Data on trepanation demographics, techniques, and survival rates were collected through the scientific analysis of more than 800 trepanned crania discovered in Peru, through field studies and the courtesy of museums and private collections in the United States and Peru, over nearly 3 decades. Data on procedures and outcomes of cranial surgery ancient, medieval, and during 19th-century through the American Civil war were obtained via a literature review. Successful trepanations from prehistoric times through the American Civil War likely involved shallow surgeries that did not pierce the dura mater. Although there are regional and temporal variations in ancient Peru, overall long-term survival rates for the study series were about 40% in the earliest period (400–200 BC), with improvement to a high of 91% in samples from AD 1000–1400, to an average of 75%–83% during the Inca Period (AD 1400s–1500). In comparison, the average cranial surgery mortality rate during the American Civil war was 46%–56%, and short- and long-term survival rates are unknown. The contrast in outcomes highlights the astonishing success of ancient cranial surgery in Peru in the treatment of living patients.