Systematic screening of autism spectrum disorder (ASD) can improve early diagnosis of ASD. We compared the efficacy of two ASD screening methods, the Global Developmental Screening (GDS), and the Modified Checklist for Autism in Toddlers-Revised, with Follow-Up (M-CHAT/F) in 1591 toddlers of ages 18-36 months from 35 government-funded clinics in south Israel. The M-CHAT/F performed better than the GDS in detecting toddlers with ASD (sensitivity: 70.0% vs. 50.0%, and specificity: 98.2% vs. 96.6% respectively). Both methods had an equivalent performance in detecting other forms of developmental delays (sensitivity = 63%; and specificity ~ 98%). In addition, remarkable inter-nurse variation was observed in the GDS referral decisions. Thus, employment of the M-CHAT/F in the Israeli health system may improve early detection of ASD among toddlers.