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Background: The influence of overall lifestyle behaviors on diabetic microvascular complications remains unknown. In addition, the potential mediating biomarkers underlying the association is unclear. This study aimed to examine the associations of the combined lifestyle factors with risks of total and individual microvascular complications among patients with type 2 diabetes (T2D) and to explore the potential mediation effects of metabolic biomarkers. Methods and findings: This retrospective cohort study included 15,104 patients with T2D free of macro- and microvascular complications at baseline (2006 to 2010) from the UK Biobank. Healthy lifestyle behaviors included noncurrent smoking, recommended waist circumference, regular physical activity, healthy diet, and moderate alcohol drinking. Outcomes were ascertained using electronic health records. Over a median of 8.1 years of follow-up, 1,296 cases of the composite microvascular complications occurred, including 558 diabetic retinopathy, 625 diabetic kidney disease, and 315 diabetic neuropathy, with some patients having 2 or 3 microvascular complications simultaneously. After multivariable adjustment for sociodemographic characteristics, history of hypertension, glycemic control, and medication histories, the hazard ratios (95% confidence intervals (CIs)) for the participants adhering 4 to 5 low-risk lifestyle behaviors versus 0 to 1 were 0.65 (0.46, 0.91) for diabetic retinopathy, 0.43 (0.30, 0.61) for diabetic kidney disease, 0.46 (0.29, 0.74) for diabetic neuropathy, and 0.54 (0.43, 0.68) for the composite outcome (all Ps-trend ≤0.01). Further, the population-attributable fraction (95% CIs) of diabetic microvascular complications for poor adherence to the overall healthy lifestyle (<4 low-risk factors) ranged from 25.3% (10.0%, 39.4%) to 39.0% (17.7%, 56.8%). In addition, albumin, HDL-C, triglycerides, apolipoprotein A, C-reactive protein, and HbA1c collectively explained 23.20% (12.70%, 38.50%) of the associations between overall lifestyle behaviors and total diabetic microvascular complications. The key limitation of the current analysis was the potential underreporting of microvascular complications because the cases were identified via electronic health records. Conclusions: Adherence to overall healthy lifestyle behaviors was associated with a significantly lower risk of microvascular complications in patients with T2D, and the favorable associations were partially mediated through improving biomarkers of glycemic control, systemic inflammation, liver function, and lipid profile. Tingting Geng and colleagues investigate whether lifestyle behaviours could affect microvascular complications among patients with type 2 diabetes in the UK Biobank. Author summary: Why was this study done?: Diabetic microvascular complications including diabetic retinopathy, diabetic neuropathy, and diabetic kidney disease have placed a significant disease burden. This study asked whether multiple lifestyle behaviors including waist circumference, smoking status, habitual diet, physical activity, and alcohol intake could jointly affect the microvascular complications, and whether the metabolic biomarkers could mediate the association. What did the researchers do and find?: In this retrospective study of 15,104 patients with type 2 diabetes, participants adhering 4 to 5 low-risk lifestyle behaviors versus 0 to 1 had a 35% lower risk of diabetic retinopathy, 57% lower risk of diabetic kidney disease, 54% lower risk of diabetic neuropathy, and 46% lower risk of the composite outcome. Our study found that albumin, HDL-C, triglycerides, apolipoprotein A, C-reactive protein, and HbA1c collectively explained 23.20% of the associations between overall lifestyle behaviors and diabetic microvascular complications. What do these findings mean?: Our findings support the importance of public health programs and interventions targeting at improving health behaviors in combination to ameliorate the risk of diabetic microvascular complications. [ABSTRACT FROM AUTHOR]