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Background Cystic echinococcosis (CE) is an important cause of human morbidity and mortality worldwide, particularly in Morocco and other North African countries. Methodology/Principal findings We investigated the potential of three strategies to reduce Echinococcus granulosus transmission: (1) 4-monthly treatment of dogs with praziquantel, (2) vaccination of sheep with the EG95 vaccine and (3) a combination of both measures. These measures were implemented during four consecutive years in different areas of the Middle Atlas Mountains in Morocco. The outcome of the interventions was assessed through hydatid cyst (viable and non-viable) counts in liver and lungs using necropsy or in vivo ultrasound examination of the liver. A total of 402 lambs were recruited for annual vaccination with the EG95 anti-E. granulosus vaccine and 395 similar lambs were selected as non-vaccinated controls. At approximately four years of age the relative risk (estimated as odds ratio) for vaccinated sheep to have viable hydatid cysts compared with non-vaccinated controls was 3% (9.37% of the vaccinated sheep were found infected while 72.82% of the controls were infected; p = 0.002). The number of viable cysts in vaccinated animals was reduced by approximately 97% (mean counts were 0.28 and 9.18 respectively; p, Author summary Cystic echinococcosis remains a major public health problem in Morocco. It is a major zoonosis affecting humans and animals caused by the larval stage of the cestode Echinococcus granulosus. The dog (final host), plays an essential role in the dissemination of eggs in the environment via its feces. The rural and poorest regions in the Middle Atlas that practice extensive sheep farming (intermediate host) are severely affected. Women and children are particularly affected by this zoonosis. Despite previous efforts done by the Moroccan authorities to reduce the incidence of infestation, these measures have been insufficient to control the disease. Through our study protocols in natural field conditions, we have shown that vaccination of the intermediate host is an effective control option in the Moroccan context, with an immune protection rate of 97%. Regular chemotherapy (4 months intervals) of owned dogs only proved to have little efficiency on incidence in sheep.