Objective To estimate the effect of out‐of‐pocket (OOP) cost on nonadherence to classes of cardiometabolic medications among patients with diabetes. Data Sources/Setting Electronic health records from a large, health care delivery system for 223,730 patients with diabetes prescribed 842,899 new cardiometabolic medications during 2006–2012. Study Design Observational, new prescription cohort study of the effect of OOP cost on medication initiation and adherence. Data Collection Adherence and OOP costs were based on pharmacy dispensing records and benefits. Principal Findings Primary nonadherence (never dispensed) increased monotonically with OOP cost after adjusting for demographics, neighborhood socioeconomic status, Medicare, medical financial assistance, OOP maximum, deductibles, mail order pharmacy incentive and use, drug type, generic or brand, day's supply, and comorbidity index; 7 percent were never dispensed the new medication when OOP cost ≥$11, 5 percent with OOP cost of $1–$10, and 3 percent when the medication was free of charge (p < .0001). Higher OOP cost was also strongly associated with inadequate secondary adherence (≥20 percent of time without adequate medication). There was no clinically significant or consistent relationship between OOP costs and early nonpersistence (dispensed once, never refilled) or later stage nonpersistence (discontinued within 24 months). Conclusions Cost‐sharing may deter clinically vulnerable patients from initiating essential medications, undermining adherence and risk factor control.