The ultimate goal of pharmaceutical care is to improve patients quality of life (QOL) by maximizing the benefits and limiting the risks associated with medication therapy. OBJECTIVE: To examine changes in QOL scores for Veteran patients receiving pharmaceutical care from clinical pharmacists. METHODS: This study was a prospective multi-site randomized controlled trial of ambulatory care clinical pharmacists' interventions for Veterans Affairs patients who were at high-risk for drug-related problems. Health related quality of life was assessed via the short form 36-item (SF-36) questionnaire. The SF-36 questionnaire was administered to patients in treatment and control groups at enrollment, 6 and 12 months. Control patients received usual medical care and intervention patients were assigned to clinical pharmacists for consultation and follow-up care. RESULTS: A total of 1054 patients were enrolled from 9 sites, 523 were randomized to the intervention group and 531 to the control group. Nine hundred fifty patients completed 6-month questionnaires and 931 completed the study. Clinical pharmacists had 1855 contacts with intervention patients. The mean number of contacts was 3.5 + 2.3. The group*time interaction term was significant for the general health perceptions (GHP) and vitality domains. The average GHP score declined 1.7 units for intervention patients compared to 5.1 units for control patients (p= 0.0066). Vitality scores declined 1.3 units for intervention and 4.2 units for control patients (p = 0.0034). CONCLUSIONS: The findings indicate ambulatory clinical pharmacists had a statistical, but not clinically meaningful, effect on HRQOL for patients at high-risk for drug-related problems.