Rationale & Objective: Reduced kidney function is strongly associated with higher mortality, but most evidence is from high-income populations. This study evaluated the relevance of kidney function to cause-specific mortality in Mexico, a country where diabetes is common and chronic kidney disease (CKD) is a major cause of morbidity and mortality. Study Design: Prospective study of Mexican adults aged ≥35 years at recruitment (1998-2004) who were followed until October 2022. Setting & Participants: Participants recruited into the Mexico City Prospective Study. Analyses focused on 126,245 participants aged 35-74 years at recruitment without prior disease (except diabetes or CKD). Exposures: Estimated glomerular filtration rate (eGFR). Outcomes: Cause-specific mortality. Analytical Approach: Cox regression was used to relate eGFR to cause-specific mortality. Analyses were adjusted for sociodemographic and lifestyle factors, anthropometry, and diabetes. Results: Among 40,996 men and 85,249 women aged 35-74 years, median eGFR was 102 (IQR, 91-110) mL/min/1.73 m2, mean body mass index was 29.1 (SD 4.9) kg/m2, 1% had self-reported CKD, 13% had previously diagnosed diabetes, and 12,590 died at ages 35-74 years over a median follow-up of 20.4 years. For those with eGFR <105 mL/min/1.73 m2, each 15-mL/min/1.73 m2 lower eGFR was associated with 32% higher all-cause mortality (RR, 1.32; 95% CI, 1.30-1.35). The strongest associations were for kidney (RR, 1.75; 95% CI, 1.69-1.80), infective (RR, 1.34; 95% CI, 1.24-1.44), and vascular deaths (RR, 1.28; 95% CI, 1.24-1.33). Compared with participants with eGFR 90-104 mL/min/1.73 m2, those with eGFR <30 mL/min/1.73 m2 had almost 7 times the all-cause mortality rate (RR, 6.5; 95% CI, 5.7-7.3). For participants with eGFR >105 mL/min/1.73 m2, higher eGFR was associated with higher mortality. The absolute excess mortality risk associated with reduced eGFR was particularly high for those with diabetes. Limitations: Data on urinary albumin and nonfatal disease outcomes were unavailable. Conclusions: In Mexico, decreased kidney function is strongly associated with premature mortality, mainly from vascular, kidney, and infective causes. Prevention and management of CKD, particularly in individuals with diabetes, should be central to disease-prevention policies. Plain-Language Summary: Evidence of the impact of decreased kidney function on the risk of death is lacking in Mexico, a country where diabetes and kidney disease are major causes of death. Between 1998 and 2004, the Mexico City Prospective Study recruited 150,000 adults aged ≥35 years and tracked their causes of death for over 20 years. This study found that decreased kidney function was linked with a higher risk of death, mainly because of heart disease, kidney disease, and infections. Individuals with substantially decreased kidney function were about 7 times more likely to die than those with apparently healthy kidney function. Having both diabetes and decreased kidney function resulted in an extremely high risk of death. Increasing the use of kidney and heart-protective drugs in people with diabetes, elevated blood pressure, or chronic kidney disease and expanding access to dialysis and kidney transplantation will likely reduce premature mortality in Mexico.