Employers have increasingly invested in workplace wellness programs to improve employee health and decrease health care costs. However, there is little experimental evidence on the effects of these programs. To evaluate a multicomponent workplace wellness program resembling programs offered by US employers. This clustered randomized trial was implemented at 160 worksites from January 2015 through June 2016. Administrative claims and employment data were gathered continuously through June 30, 2016; data from surveys and biometrics were collected from July 1, 2016, through August 31, 2016. There were 20 randomly selected treatment worksites (4037 employees) and 140 randomly selected control worksites (28 937 employees, including 20 primary control worksites [4106 employees]). Control worksites received no wellness programming. The program comprised 8 modules focused on nutrition, physical activity, stress reduction, and related topics implemented by registered dietitians at the treatment worksites. Four outcome domains were assessed. Self-reported health and behaviors via surveys (29 outcomes) and clinical measures of health via screenings (10 outcomes) were compared among 20 intervention and 20 primary control sites; health care spending and utilization (38 outcomes) and employment outcomes (3 outcomes) from administrative data were compared among 20 intervention and 140 control sites. Among 32 974 employees (mean [SD] age, 38.6 [15.2] years; 15 272 [45.9%] women), the mean participation rate in surveys and screenings at intervention sites was 36.2% to 44.6% (n = 4037 employees) and at primary control sites was 34.4% to 43.0% (n = 4106 employees) (mean of 1.3 program modules completed). After 18 months, the rates for 2 self-reported outcomes were higher in the intervention group than in the control group: for engaging in regular exercise (69.8% vs 61.9%; adjusted difference, 8.3 percentage points [95% CI, 3.9-12.8]; adjusted P = .03) and for actively managing weight (69.2% vs 54.7%; adjusted difference, 13.6 percentage points [95% CI, 7.1-20.2]; adjusted P = .02). The program had no significant effects on other prespecified outcomes: 27 self-reported health outcomes and behaviors (including self-reported health, sleep quality, and food choices), 10 clinical markers of health (including cholesterol, blood pressure, and body mass index), 38 medical and pharmaceutical spending and utilization measures, and 3 employment outcomes (absenteeism, job tenure, and job performance). Among employees of a large US warehouse retail company, a workplace wellness program resulted in significantly greater rates of some positive self-reported health behaviors among those exposed compared with employees who were not exposed, but there were no significant differences in clinical measures of health, health care spending and utilization, and employment outcomes after 18 months. Although limited by incomplete data on some outcomes, these findings may temper expectations about the financial return on investment that wellness programs can deliver in the short term. ClinicalTrials.gov Identifier: NCT03167658.