Background: Patients with chronic kidney disease (CKD) who are hospitalized with a critical illness are at increased risk for adverse outcomes. We studied the predictors of hospitalization with critical illness among patients with non-dialysis-dependent CKD stages 3 and 4 in a safety-net healthcare setting. Methods: A retrospective cohort study was conducted among patients ≥18 years of age with CKD stages 3 and 4 using a CKD registry from a safety-net healthcare system. Hospitalizations with critical illness were identified among patients requiring nonelective admission or transfer to the intermediate or intensive care unit during a 3-year period after the diagnosis of CKD. Poisson regression was used to determine associations between baseline characteristics and hospitalization requiring intermediate or intensive care among all CKD patients and in those with different stages of CKD. Outcomes of these hospitalizations were also tabulated. Results: Among 8,302 patients with CKD stages 3 and 4, 1,298 were hospitalized and 495 required intermediate or intensive care during a 3-year follow-up period. In the adjusted analysis, advanced CKD, Hispanics (incident rate ratio [IRR]: 1.88), non-Hispanic Blacks (IRR: 1.48), presence of congestive heart failure (IRR: 2.09), cardiovascular disease (IRR: 1.57), chronic pulmonary disease (IRR: 1.60), liver disease, malignancy, and anemia were associated with higher risk of hospitalization requiring intermediate or intensive care. The association of age, gender, race/ethnicity, congestive heart failure, anemia, and body mass index with hospitalization requiring intermediate or intensive care differed significantly by CKD stage (p value for interaction term <0.05). Congestive heart failure and severity of anemia were associated with a higher risk of hospitalization requiring intermediate or intensive care among patients with mild CKD, and the magnitude of association attenuated among patients with advanced CKD. Conclusions: The burden of hospitalization with critical illness among patients with non-dialysis-dependent CKD stages 3 and 4 remains high and was associated with demographic factors and comorbid medical conditions, especially among those with congestive heart failure and cardiovascular disease. Targeted, effective interventions to reduce the burden of hospitalization and critical illness in CKD patients within safety-net healthcare systems are needed.