The aim of the study was to assess patients' attitudes towards and experiences of generic substitution 3 years after generic substitution of prescription medicines was permitted in Norway. Prescriptions from 2,128 consecutive patients in a Norwegian pharmacy were retrospectively reviewed to identify all patients (n=274) receiving eight or more different prescription drugs on the fifth level in the Anatomical Therapeutic Chemical (ATC) classification system during the last 6 months. An age-adjusted control group (n=269) of patients receiving three to seven different prescription drugs was randomly selected. Of the 543 patients, 386 were eligible for inclusion. Both groups received a mailed questionnaire addressing their experiences with and attitudes towards generic substitution. The overall response rate was 73% (281/386) and the average age of the respondents was 66 years old. The study found that patients who reported to have received information from their physician or the pharmacy about generic substitution were more likely to have switched (P<0.001). About half (138/281) of the patients had experienced a generic switch, and a higher proportion of the polypharmacy patients had their medication substituted compared to the control patients (P<0.001). Altogether 50 (36%) of the patients who had experienced a switch, reported one or more negative experiences connected to the substitution, and 29 of these (21%) reported an overall negative experience after the change. The experiences of the patients were not related to age, gender, or number of medications or information about generics from either the pharmacy or the physician. About 41% of the patients would not switch if they had no personal economic incentives. About 1/3 of the patients who had their medication substituted reported negative experiences. Generic drug substitution for a number of patients is not considered an equal alternative to branded drugs, and these patients may need additional information and support. The lack of correlation between patient experiences and age, gender, and medical regimen complexity is interesting and should be investigated further.