Fluid administration has been reported to be associated with an increased risk of acute kidney injury (AKI). We assessed whether, after correction for fluid balance, amount and chloride content of fluids administered have an independent association with AKI. We performed an observational study in patients after major surgery assessing the independent association of AKI with volume, chloride content and fluid balance, after adjustment for Physiological and Operative Severity Score for enUmeration of Mortality and morbidity (POSSUM) score, age, elective versus emergency surgery, and duration of surgery. We studied 542 consecutive patients undergoing major surgery. Of these, 476 patients had renal function tested as part of routine clinical care and 53 patients (11.1%) developed postoperative AKI. After adjustments, a 100 ml greater mean daily fluid balance was artificially associated with a 5% decrease in the instantaneous hazard of AKI: adjusted Hazard Ratio (aHR) 0.951, 95% confidence intervals (CI) 0.935 to 0.967, <i>P</i> <0.001. However, after adjustment for the proportion of chloride-restrictive fluids, mean daily fluid amounts and balances, POSSUM morbidity, age, duration and emergency status of surgery, and the confounding effect of fluid balance, every 5% increase in the proportion of chloride-liberal fluid administered was associated with an 8% increase in the instantaneous hazard of AKI (aHR 1.079, 95% CI 1.032 to 1.128, <i>P</i>=0.001), and a 100 ml increase in mean daily fluid amount given was associated with a 6% increase in the instantaneous hazard of AKI (aHR 1.061, 95% CI 1.047 to 1.075, <i>P</i> <0.001). After adjusting for key risk factors and for the confounding effect of fluid balance, greater fluid administration and greater administration of chloride-rich fluid were associated with greater risk of AKI.