Objectives The All Wales Medicines Strategy Group (AWMSG) appraises the clinical and cost effectiveness of new medicines being considered for National Health Service (NHS) prescribing in Wales (UK). The aim of this study was to compare the estimated expenditure on selected medicines submitted by pharmaceutical companies for appraisal with the observed expenditure on these medicines following recommendation. Methods Medicines appraised and recommended for use in NHS Wales by AWMSG between May 2005 and December 2013 were identified for inclusion in the study. Estimates of expenditure were obtained from company submissions to AWMSG. Primary and secondary care dispensing databases were used to obtain observed expenditure. The Wilcoxon matched-pairs signed rank test was used to compare the observed and estimated expenditure in each of the 3 years after introduction of the medicine. Results Forty-nine medicines appraised and recommended by AWMSG during the period of interest were included in the study. Median estimated and observed expenditure in each of the 3 years post-recommendation were as follows: year 1 £86,400 and £47,300; year 2 £175,500 and £73,200; year 3 £212,100 and £78,900 ( p = 0.03, p = 0.006 and p = 0.001, respectively). The expenditure on 42 of the 49 medicines (82%) was overestimated in at least one of the 3 years post-introduction, with 32 (65%) overestimated in all 3 years. Conclusion In their applications for health technology appraisal, pharmaceutical companies tended to overestimate the expenditure of the majority of medicines recommended by AWMSG. These findings have implications for the assessment of predicted expenditure as part of the process of medicines appraisal in Wales.