The response to heartworm infection before preventative programs were started was investigated in 56 dogs. Dogs were infected with third-stage larvae of Dirofilaria immitis and started on preventative programs (monthly treatment) with ivermectin/pyrantel pamoate (IVM/PP) or milbemycin oxime (MO) 3.5, 4.5, 5.5, or 6.5 months after infection. Each time period comprised a group of six dogs treated with IVM/PP and six treated with MO. Thoracic radiographs were obtained prior to infection, at the start of preventative treatment, and at regular intervals until dogs were necropsied 1 year after the preventative was started. All dogs developed radiographic signs of heartworm disease, and all had heartworm-related arterial changes at necropsy. From Day 210 to 330, interstitial lung disease was less severe in dogs started on MO 3.5 months after infection than in dogs given IVM/PP at the same time. Arterial surfaces were more severe at necropsy in the dogs started on MO at 4.5 months than in the dogs started on IVM/PP at the same time. There was increased caudal lobar arterial and interstitial disease in the dogs treated with IVM/PP compared with dogs treated with MO; this was attributed to the death of young worms within the caudal pulmonary arteries. Dogs started on either preventative at 5.5 and 6.5 months after infection had radiographic changes and necropsy evaluations that were similar to those of untreated controls. This study reinforces the recommendation of the American Heartworm Society that mature dogs be evaluated for infection prior to starting a monthly preventative and that any dog that tests positive by a heartworm antigen test receive treatment with an adulticide prior to starting a heartworm preventative program.