Background Elevated total serum alkaline phosphatase (ALP) levels have been associated with mortality in the general population and in dialysis patients. Study Design Retrospective cohort study. Setting & Participants 28,678 patients with chronic kidney disease (CKD) stages 3 and 4 (estimated glomerular filtration rate, 15-59 mL/min/1.73 m2 ) were identified using the Cleveland Clinic CKD Registry. CKD was defined as 2 estimated glomerular filtration rate values <60 mL/min/1.73 m2 drawn more than 90 days apart using the CKD-EPI (CKD Epidemiology Collaboration) creatinine equation. Predictor ALP levels measured using the calorimetric assay were examined as quartiles (quartile Q1, <66 U/L; Q2, 66-81 U/L; Q3, 82-101 U/L; and Q4, ≥102 U/L) and as a continuous measure. Outcomes & Measurements All-cause mortality and end-stage renal disease (ESRD) were ascertained using the Social Security Death Index and US Renal Data System. Results After a median follow-up of 2.2 years, 588 patients progressed to ESRD and 4,755 died. There was a graded increase in risk of mortality with higher ALP quartiles (Q2, Q3, and Q4) compared to the reference quartile (Q1) after adjusting for demographics, comorbid conditions, use of relevant medications, and liver function test results. The highest ALP quartile was associated with an HR for ESRD of 1.38 (95% CI, 1.09-1.76). Each 1-SD (42.7 U/L) higher ALP level was associated with 15% (95% CI, 1.09-1.22) and 16% (95% CI, 1.14-1.18) increased risk of ESRD and mortality, respectively. Limitations Single-center observational study; lack of complete data, including parathyroid hormone level, for all study participants, and attrition bias. Conclusions Higher serum ALP levels in patients with CKD stages 3-4 were associated independently with all-cause mortality and ESRD.