We investigated the effects of deep-frying or oven cooking on inactivation of Shiga toxin-producing cells of Escherichia coli (STEC) in meatballs. Finely ground veal and/or a finely ground beef-pork-veal mixture were inoculated (ca. 6.5 log CFU/g) with an eight-strain, genetically marked cocktail of rifampin-resistant STEC strains (STEC-8; O111:H, O45:H2, O103:H2, O104:H4, O121:H19, O145:NM, O26:H11, and O157:H7). Inoculated meat was mixed with liquid whole eggs and seasoned bread crumbs, shaped by hand into 40-g balls, and stored at -20°C (i.e., frozen) or at 4°C (i.e., fresh) for up to 18 h. Meatballs were deep-fried (canola oil) or baked (convection oven) for up to 9 or 20 min at 176.7°C (350°F), respectively. Cooked and uncooked samples were homogenized and plated onto sorbitol MacConkey agar with rifampin (100 μg/ml) followed by incubation of plates at 37°C for ca. 24 h. Up to four trials and three replications for each treatment for each trial were conducted. Deep-frying fresh meatballs for up to 5.5 min or frozen meatballs for up to 9.0 min resulted in reductions of STEC-8 ranging from ca. 0.7 to ≥6.1 log CFU/g. Likewise, reductions of ca. 0.7 to ≥6.1 log CFU/g were observed for frozen and fresh meatballs that were oven cooked for 7.5 to 20 min. This work provides new information on the effect of prior storage temperature (refrigerated or frozen), as well as subsequent cooking via deep-frying or baking, on inactivation of STEC-8 in meatballs prepared with beef, pork, and/or veal. These results will help establish guidelines and best practices for cooking raw meatballs at both food service establishments and in the home.