The donation of ivermectin (Mectizan, Merck & Co., Inc.) to control onchocerciasis (river blindness) was established in 1987 and has since gradually expanded to provide for >570 million treatments cumulatively over the past 20 years. The Mectizan Donation Program (MDP) operates within a broad partnership in 33 endemic countries in need of mass treatment. Particular operational methods and tools are applied to facilitate ivermectin mass treatment. Drug management has been streamlined, including dosing, tablet size and packaging, and monitoring for adverse events. Much of the experience gained in the development of ivermectin mass treatment can be usefully applied in the recent broader perspective of control of neglected tropical diseases. The most important operational lessons of the MDP include: (i) the need to easily define the target population for treatment using rapid, non-invasive techniques; (ii) the value of a broad partnership; (iii) the great potential of working through community-directed treatment; (iv) the need to streamline all drug management aspects and (v) the importance of operations research to tackle new challenges.