Worldwide, adherence to national guidelines for physical activity (PA), and fruit and vegetable consumption is recommended to promote health and reduce the risk for (chronic) disease. This study reports on the effectiveness of various social-cognitive interventions to improve adherence to guidelines and the revealed adherence predictors. Participants (n = 1,629), aged 45–70 years, randomly selected and recruited in 2005–2006 from 23 Dutch general practices, were randomized (centralized stratified allocation) to four groups to receive a 12-month lifestyle intervention targeting guideline adherence for PA and fruit and vegetable consumption. Study groups received either four computer-tailored print communication (TPC) letters (n = 405), four telephone motivational interviewing (TMI) sessions (n = 407), a combined intervention (two TPC letters and two TMI sessions, n = 408), or no intervention (control group, n = 409). After the baseline assessment, all parties were aware of the treatment groups. Outcomes were measured with self-report postal questionnaires at baseline, 25, 47 and 73 weeks. For PA, all three interventions were associated with better guideline adherence than no intervention. Odds ratios for TPC, TMI and the combined intervention were 1.82 (95% CI 1.31; 2.54), 1.57 (95% CI 1.13; 2.18), and 2.08 (95% CI 1.50; 2.88), respectively. No pedometer effects were found. For fruit and vegetable consumption, TPC seemed superior to those in the other groups. Odd ratio for fruit and vegetable consumption were 1.78 (95% CI 1.32; 2.41) and 1.73 (95% CI 1.28; 2.33), respectively. For each behaviour, adherence was predicted by self-efficacy expectations, habit strength and stages of change, whereas sex, awareness and the number of action plans predicted guideline adherence for fruit and vegetable intake. The season predicted the guideline adherence for PA and fruit consumption. The odds ratios revealed were equivalent to modest effects sizes, although they were larger than those reported in systematic reviews. This study indicated that less resource intensive interventions might have the potential for a large public health impact when widely implemented. The strengths of this study were the participation of lower educated adults and evaluation of maintenance effects. (Trial NL1035, 2007-09-06).