OBJECTIVES:   Estimate direct and indirect costs generated by eight diseases related to O&O in Mexican population for the period 1999-2023. METHODS: Data on diabetes, cardiovascular disorders (CVD), osteoartritis, and malignant tumors (esophagus, pancreas, breast, cervix, colo-rectal) are analyzed for 2004-2013. Cost of illness approach was used for direct cost estimates; Indirect costs are estimated by the human capital approach that includes lost income for premature death (LIPD), temporary disability subsidies (TDS), permanent disability pension (PDP) and opportunity cost for the non-medical care giver (OCC). RESULTS: Annual average direct costs generated by selected diseases related to O&O represented 17% of the total public medical care expenditure (0.1% of GDP) of 2013. Diabetes and CVD contributed with 80% of such costs. Annual average indirect costs represented 0.2% of GDP of 2013 and are dominated by LIPD (64%) followed by PDP (19%) and OCC (10%). CONCLUSIONS: Findings show the need of continue efforts to address the challenge posed by O&O for both the Mexican health care system in terms of financial sustainability and the Mexican society as a whole in terms of significant reductions in productivity in the short and midterms. Of particular relevance is the recent implementation of the National Strategy to Prevent and Control O&O and Diabetes which should be monitored and evaluated in order to document effectiveness of public policy interventions in the O&O arena for the Mexican case.