BACKGROUND Subclinical hypothyroidism (SCH) has been associated with ischemic heart disease (IHD); however, it is unknown whether treatment of SCH with levothyroxine sodium will reduce the risk of IHD. The aim of this study was to investigate the association between levothyroxine treatment of SCH with IHD morbidity and mortality. METHODS We used the United Kingdom General Practitioner Research Database to identify individuals with new SCH (serum thyrotropin levels of 5.01-10.0 mIU/L and normal free thyroxine levels) recorded during 2001 with outcomes analyzed until March 2009. All analyses were performed separately for younger (40-70 years) and older (>70 years) individuals. Hazard ratios (HRs) for IHD events (fatal and nonfatal) were calculated after adjustment for conventional IHD risk factors, baseline serum thyrotropin levels, and initiation of levothyroxine treatment as a time-dependent covariate. RESULTS Subclinical hypothyroidism was identified in 3093 younger and 1642 older individuals. For a median follow-up period of 7.6 years, 52.8% and 49.9% of younger and older patients with SCH were treated with levothyroxine, respectively. There were 68 incident IHD events in 1634 younger patients treated with levothyroxine (4.2%) vs 97 IHD events in 1459 untreated individuals (6.6%) (multivariate-adjusted HR, 0.61; 95% CI, 0.39-0.95). In contrast, in the older group there were 104 events in 819 treated patients (12.7%) vs 88 events in 823 untreated individuals (10.7%) (HR, 0.99; 95% CI, 0.59-1.33). CONCLUSIONS Treatment of SCH with levothyroxine was associated with fewer IHD events in younger individuals, but this was not evident in older people. An appropriately powered randomized controlled trial of levothyroxine in SCH examining vascular outcomes is now warranted.