In this randomized controlled economic evaluation we compared guided asthma self-management with usual asthma care according to guidelines for Dutch family physicians. Nineteen family practices were randomized, and 193 adults with stable asthma (98 self-management, 95 usual care) were included and monitored for 2 years. We hypothesized that introducing self-management would not compromise asthma control and cost would be equal to or lower than in usual care. Patient-specific cost data were collected, preference-based utilities were assessed, and incremental cost per quality-adjusted life year (QALY) and successfully treated week gained was calculated. Self-management patients gained 0.039 QALY (95% confidence interval [CI], 0.003 to 0.075) and experienced 81 (95% CI, 78 to 84) successfully treated weeks in 2 years' time; the corresponding figures for usual care were 0.024 (95% CI, -0.022 to 0.071) and 75 (95% CI, 72 to 78). Total costs were 1,084 euros(95% CI, 938 to 1,228) for self-management and 1,097 euros (95% CI, 933 to 1,260) for usual care. Self-management patients consumed 1,680 (95% CI, 1,538 to 1,822) puffs of budesonide, usual care patients 1,897 (95% CI, 1,679 to 2,115). Mean productivity cost due to limited activity days was 213 euros lower among self-management patients. When all costs were included, self-management was cost-effective on all outcomes. The probability that self-management was cost-effective relative to usual care in terms of QALYs was 52%. We conclude that guided self-management is a safe and efficient alternative approach compared with asthma treatment usually provided in Dutch primary care.