A coral reef system at the Steinhart Aquarium in San Francisco, CA, USA experienced a population explosion of pycnogonid sea spiders (Arthropoda: Class Pycnogonida) with subsequent deleterious health effects on the corals in the system. Sixteen coral colonies across three species (Stylophora pistillata, Pocillopora damicornis, and Acropora tenuis) were chosen from this system for milbemycin oxime immersion therapy trials, with the goal of decreasing or eradicating the sea spider population with minimal detrimental effect to the corals. Corals underwent two milbemycin immersion treatments, administered 1 wk apart, at the previously published aquatic invertebrate dose of 0.016 parts per million (ppm; mg/L), but therapy did not reduce the number of sea spiders. Doubling the dose to 0.032 ppm milbemycin and repeating this immersion therapy 1/wk for three treatments successfully reduced the sea spiders. Histopathology was used to assess the health of the corals and tolerance to therapy, and posttreatment biopsies confirmed that there were no adverse effects to any of the three species of coral. Repeated 1/ wk treatments of milbemycin oxime immersion therapy at 0.032 ppm appears to be both safe and effective for reducing the numbers of pycnogonid sea spiders in the stony corals S. pistillata, P. damicornis, and A. tenuis.