Background: Contrast-induced acute kidney injury (AKI) is a significant cause of morbidity and mortality among hospitalized patients. However, data regarding the long-term prognostic implications of reversible AKI following contrast exposure are limited. Methods: We carried out a prospective 5-year follow-up study of 78 patients with chronic kidney disease who underwent coronary angiography, employing a uniform intravenous hydration protocol supplemented by either acetylcysteine (600 mg orally t.i.d.) or placebo. Results: Contrast-induced AKI (defined as ≥0.5 mg/dl increase in serum creatinine, SCr, or >25% increase above baseline 48 h following contrast exposure) developed in 10 of the 78 patients (13%). All SCr changes were reversible, and were no longer evident 7 days following contrast exposure. At 5 years of follow-up, mortality rates were significantly higher among patients who developed reversible AKI (90%) as compared with those who did not (32%; p < 0.001). Accordingly, multivariable analysis demonstrated that reversible AKI was independently associated with a significant 2.7-fold increase (p = 0.001) in the risk of long-term mortality. Conclusions: Our findings indicate that short-term reductions in renal function following contrast exposure have important long-term prognostic implications in patients with chronic kidney disease. Careful follow-up of SCr levels following contrast exposure is warranted for long-term risk assessment in this population.