An estimated 60% of individuals prescribed lipid-lowering medications are nonadherent. Failure to adhere increases morbidity, mortality, healthcare utilization, and healthcare costs. This study examined the effectiveness of a population-based, individualized Transtheoretical Model (TTM) expert system intervention to improve adherence and increase exercise and diet in a randomized 18-month trial involving 404 adults. Compared to usual care, treatment participants who started in a pre-action stage were significantly more likely to be in the Action and Maintenance (A/M) stages for adherence at end of treatment (55.3% versus 40%, z = 2.11, p < 0.05, h = 0.31) and at 18-months (56% versus 37.8%, z = 2.38, p < 0.01, h = 0.36). The treatment group scored significantly better on two measures of adherence at six and 12 months post-treatment (all p < 0.05, odds ratios [OR] 1.49-3.67). Among those who began in A/M, treatment participants were significantly more likely to remain in A/M at 18 months (85.2% versus 55.6%, z = 2.63, p < 0.01, h = 0.67). Those receiving treatment were significantly more likely to progress to A/M for exercise and dietary fat reduction (43.3% versus 24.7% for exercise, and 24.7% versus 12.5% for diet). TTM expert system interventions can have a significant impact on entire populations for adherence. Results for dietary fat and exercise suggest covariation of treatment effects.