OBJECTIVE: Comparative effectiveness research methods are used to compare the effect of four distinct glucose-control strategies on subsequent myocardial infarction and nephropathy in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 58,000 adults with type 2 diabetes and A1C <7% (53 mmol/mol) while taking two or more oral agents or basal insulin had subsequent A1C >/=7% (53 mmol/mol) to 8.5% (69 mmol/mol). Follow-up started on date of first A1C >/=7% and ended on date of a specific clinical event, death, disenrollment, or study end. Glucose-control strategies were defined as first intensification of glucose-lowering therapy at A1C >/=7, >/=7.5, >/=8, or >/=8.5% with subsequent control for treatment adherence. Logistic marginal structural models were fitted to assess the discrete-time hazards for each dynamic glucose-control strategy, adjusting for baseline and time-dependent confounding and selection bias through inverse probability weighting. RESULTS: After adjustment for age, sex, race/ethnicity, comorbidities, blood pressure, lipids, BMI, and other covariates, progressively more aggressive glucose-control strategies were associated with reduced onset or progression of albuminuria but not associated with significant reduction in occurrence of myocardial infarction or preserved renal function based on estimated glomerular filtration rate over 4 years of follow-up. CONCLUSIONS: In a large representative cohort of adults with type 2 diabetes, more aggressive glucose-control strategies have mixed short-term effects on microvascular complications and do not reduce the myocardial infarction rate over 4 years of follow-up. These findings are consistent with the results of recent clinical trials, but confirmation over longer periods of observation is needed.