Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM). To assess 1-year efficacy and safety of salsalate in T2DM. Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (ClinicalTrials.gov: NCT00799643). 3 private practices and 18 academic centers in the United States. Persons aged 18 to 75 years with fasting glucose levels of 12.5 mmol/L or less (≤225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% who were treated for diabetes. 286 participants were randomly assigned (between January 2009 and July 2011) to 48 weeks of placebo (n = 140) or salsalate, 3.5 g/d (n = 146), in addition to current therapies, and 283 participants were analyzed (placebo, n = 137; salsalate, n = 146). Change in hemoglobin A1c level (primary outcome) and safety and efficacy measures. The mean HbA1c level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, -0.53% to -0.21%; P < 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged. Trial duration and number of patients studied were insufficient to determine long-term risk-benefit of salsalate in T2DM. Salsalate improves glycemia in patients with T2DM and decreases inflammatory mediators. Continued evaluation of mixed cardiorenal signals is warranted.