BACKGROUND: Patients with acute coronary syndrome without standard modifiable cardiovascular risk factors (SMuRFs; hypertension, smoking, dyslipidemia, diabetes) have not been well studied, with little known about their characteristics, quality of care, or outcomes. We sought to systematically analyze patients with ACS without SMuRFs, especially to evaluate the effectiveness of guideline-directed medical therapy for these patients. METHODS AND RESULTS: In the CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) project (2014-2019), we examined the presence and absence of SMuRFs and features among 89 462 patients with initial acute coronary syndrome. The main outcome was in-hospital all-cause mortality. Among eligible patients, 11.0% had none of the SMuRFs (SMuRF-less). SMuRF-less patients had higher in-hospital mortality (unadjusted hazard ratio [HR], 1.49 [95% CI, 1.19-1.87]). After adjustment for clinical characteristics and treatments, the associations between SMuRF status and in-hospital mortality persisted (adjusted HR, 1.35 [95% CI, 1.07-1.70]). Guideline-directed optimal medical therapy (receiving angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and statins) was not associated with lower mortality (adjusted HR, 0.98 [95% CI, 0.58-1.67]) in SMuRF-less patients, unlike the association in patients with SMuRFs (adjusted HR, 0.80 [95% CI, 0.66-0.98]). Sensitivity analyses were consistent with these results. CONCLUSIONS: SMuRF-less patients were associated with an increased risk of in-hospital mortality. Guideline-directed medical therapy was less effective in SMuRF-less patients than in patients with SMuRFs. Dedicated studies are needed to confirm the optimal therapy for SMuRF-less patients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02306616.