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.