Polypharmacy regimens may increase the susceptibility of older adults to micronutrient inadequacy and deficiency via impairment of nutritional status. We hypothesized that a multi-vitamin-mineral supplement (MVMS) could improve nutritional status in older adults prescribed diuretics, metformin, and/or proton pump inhibitors (PPIs). We conducted a randomized, double-blind, placebo controlled, parallel clinical trial in which eligible subjects were instructed to consume either a MVMS or placebo for 16 wk. Fasting blood was collected at baseline, 8, and 16 wk and the status of selected vitamins and minerals determined. Thirty-five and 19 men and women aged 45-75 yrs in the in MVMS and placebo arms, respectively, completed the trial. The mean total number of medications among the three drug classes taken by participants did not differ between two groups. The status of vitamins B1, B12, C and folate and calcium, copper, magnesium and zinc at baseline were within normal ranges. The MVMS group had a greater change in nutrient status after 16 wk compared to the placebo group for serum folate (7.5 vs.-1.6 ng/mL, p < 0.0001), vitamin B12 (159.2 vs.-33.9 pg/mL, p ¼ 0.007), and plasma vitamin C (0.2 vs. 0.0 mg/dL, p ¼ 0.004). Other measured vitamins and minerals were not significantly changed during the intervention. In conclusion, the status of vitamins B12, C and folate improved with MVMS but remained within normal ranges in older adults taking diuretics, metformin, and/or PPIs.