Background: The role of post-mastectomy radiotherapy (PMRT) for breast cancer is controversial when 3-or-less lymph nodes are metastatic. Apart from local control, survival and toxicity, cost also plays an important role in decision-making. Methods: A Markov model was designed to assess cost, health outcomes and cost-effectiveness of different radiotherapy techniques for management of PMRT patients. Thirty-nine scenarios were modelled based on type of radiotherapy, laterality, pathologic nodal burden, and dose fractionation. We considered a societal perspective, lifetime horizon and a 3% discount rate. The data on quality of life (QoL) was derived using the cancer database on cost and QoL. Published data on cost of services delivered in India were used. Findings: Post-mastectomy radiotherapy results in incremental quality adjusted life years (QALYs) that ranged from -0.1 to 0.38 across different scenarios. The change in cost ranged from estimated median savings of USD 62 (95% confidence intervals: -168 to -47) to incurring an incremental cost of USD 728 (650-811) across different levels of nodal burden, breast laterality and dose fractionation. For women with node-negative disease, disease-specific systemic therapy remains to be the preferred strategy. For women with node-positive disease, two-dimensional radiotherapy (2DRT) with hypofractionation is the most cost-effective strategy. However, a CT based planning is preferred when maximum heart distance (MHD) >1cm, irregular chest wall contour and inter-field separation >18cm. Interpretation: PMRT is cost-effective for all node-positive patients. With similar toxicity and effectiveness profile compared with conventional fractionation, moderate hypofractionation significantly reduces the cost of treatment and should be the standard of care. Conventional techniques for PMRT are cost-effective over newer modalities which provide minimal additional benefit, at high cost. Funding: The funding to collect primary data for study was provided by Department of Health Research, Ministry of Health and Family Welfare, New Delhi, wide letter number F. No. T.11011/02/2017-HR/3100291.