Purpose The rapidly increasing burden of cancer in India has profound impacts on health care costs for patients and their families. High out-of-pocket (OOP) expenditure, lack of insurance, and low government expenditure create a vicious cycle, leading to household impoverishment. Complex cancer surgery is now increasingly important for emerging countries; however, little is understood about the macro- and microeconomics of these procedures. After the Lancet Oncology Commission on Global Cancer Surgery, we evaluated the OOP expenditure for patients undergoing pancreatico-duodenectomy (PD) at a government tertiary cancer center in India. Methods Prospective data from 98 patients who underwent PD between January 2014 and June 2015 were collected and analyzed. The time frame for consideration of expenses, including all preoperative investigations, was from the first hospital visit to the day of discharge. Catastrophic expenditure was calculated by assessing the percentage of households in which OOP health payments exceeded 10% of the total household income. Results The mean expenditure for PD by patients was Rs.295,679.57 (US$74,420, purchasing power parity corrected). This amount was significantly higher among those admitted to a private ward and those with complications. Only 29.6% of the patients had insurance coverage. A total of 76.5% of the sample incurred catastrophic expenditure, and 38% of those with insurance underwent financial catastrophe compared with 93% of those without insurance. The percentage of patients facing catastrophic impact was highest among those in semiprivate wards, at 86.7%, followed by those in public and private wards. Conclusion The cost of PD is high and is often unaffordable for a majority of India’s population. A review of insurance coverage policies for better coverage must be considered.