BACKGROUND: Large observational datasets such as Clinical Practice Research Datalink (CPRD) provide opportunities to conduct clinical studies and economic evaluations with efficient designs. OBJECTIVES: Our objectives were to report the economic evaluation methodology for a cluster randomised controlled trial (RCT) of a UK NHS-delivered public health intervention for children with asthma that was evaluated using CPRD and describe the impact of this methodology on results. METHODS: CPRD identified eligible patients using predefined asthma diagnostic codes and captured 1-year pre- and post-intervention healthcare contacts (August 2012 to July 2014). Quality-adjusted life-years (QALYs) 4 months post-intervention were estimated by assigning utility values to exacerbation-related contacts; a systematic review identified these utility values because preference-based outcome measures were not collected. Bootstrapped costs were evaluated 12 months post-intervention, both with 1-year regression-based baseline adjustment (BA) and without BA (observed). RESULTS: Of 12,179 patients recruited, 8190 (intervention 3641; control 4549) were evaluated in the primary analysis, which included patients who received the protocol-defined intervention and for whom CPRD data were available. The intervention's per-patient incremental QALY loss was 0.00017 (bias-corrected and accelerated 95% confidence intervals [BCa 95% CI] -0.00051 to 0.00018) and cost savings were £14.74 (observed; BCa 95% CI -75.86 to 45.19) or £36.07 (BA; BCa 95% CI -77.11 to 9.67), respectively. The probability of cost savings was much higher when accounting for BA versus observed costs due to baseline cost differences between trial arms (96.3 vs. 67.3%, respectively). CONCLUSION: Economic evaluations using data from a large observational database without any primary data collection is feasible, informative and potentially efficient. Clinical Trials Registration Number: ISRCTN03000938.