The effect of early adherence on long-term viral suppression was assessed among 1281 patients with HIV starting a protease inhibitor-containing regimen in 1997-1999, followed up to 12 years. Association between 4-month adherence (3-level score) and prolonged viral suppression was evaluated using a multivariate mixed logistic model in 891 eligible patients. High 4-months adherence [odds ratio (95% confidence interval): 3.72 (1.98 to 6.98)] was associated with long-term prolonged viral suppression, irrespective of maintenance adherence. This unexpected long-term virological impact of early adherence reinforces the message that, when starting antiretrovirals, all means should be mobilized to ensure optimum early adherence to achieve prolonged antiretroviral success.