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Generic health-related quality-of-life (QoL) instruments are increasingly used to assess the outcomes of surgical interventions. However, it is unclear to what extent the patient's associated comorbidities have on the responsiveness of these instruments to measure changes caused by the operation. The purpose of this study was to assess the relative influence of comorbidities to surgical disease in how patients answered the items of the most frequently used generic instrument, the SF-36. Sixty-nine preoperative patients completed the SF-36, which contains 36 items covering eight domains and a health transition question. For each of the 36 items, patients were asked to rate the influence of their surgical disease and their comorbidities on how they answered the items from 1 to 10. The surgical disease, comorbidities, and medications were recorded. Data was analyzed using the Mann-Whitney U test and linear regression analysis. Of the 36 items of the SF-36, patients reported that their surgical disease influences nine items greater than their comorbidities (P < 0.05). Using linear regression analysis, the number of comorbidities did not effect the influence of the surgical disease in any item; however, this number had a direct relationship (P < 0.05) with the influence of comorbidities on how the patient answered the item. However, the magnitude of the influence was low. There was an inverse (negative slope, P < 0.05) relationship between the number of comorbidities and the score of six of eight domains. Although the surgical disease has more of an influence on how patients answered the items of the SF-36, as the number of comorbidities increased, these seem to have more influence. Therefore, the SF-36 would be a good choice for assessing QoL in most surgical disease. However, as the overall magnitude of this influence was low, this may be a cause of the lack of responsiveness of generic QoL instruments in measuring the effect of operations on QoL. Importantly, as the number of comorbidities increased, the scores of the SF-36 decreased, implying that the effect of the surgical disease would be greater in patients with fewer comorbidities.