OBJECTIVE To determine the effectiveness of metronomic cyclophosphamide (MC) chemotherapy (primary treatment of interest) with adjuvant meloxicam administration as maintenance treatment for dogs with appendicular osteosarcoma following limb amputation and carboplatin chemotherapy. DESIGN Retrospective case series with nested cohort study. ANIMALS 39 dogs with a histologic diagnosis of appendicular osteosarcoma that underwent limb amputation and completed carboplatin chemotherapy from January 2011 through December 2015. PROCEDURES Dogs were grouped by whether carboplatin chemotherapy had been followed with or without MC chemotherapy (15 mg/m2, PO, q 24 h) and meloxicam (0.1 mg/kg [0.045 mg/lb], PO, q 24 h). The Breslow rank test was used to assess whether MC chemotherapy was associated with overall survival time (OST) and disease progression-free time (PFT) after limb amputation. RESULTS 19 dogs received carboplatin and MC chemotherapy, and 20 dogs received only carboplatin chemotherapy. No differences were identified between these groups regarding age, reproductive status, body weight, serum alkaline phosphatase activity, tumor location, or histologic grade or subtype of osteosarcoma. Median duration of MC chemotherapy for dogs in the carboplatin-MC group was 94 days (range, 7 to 586 days); this treatment was discontinued for 11 (58%) dogs when cystitis developed. Overall, 11 (28%) dogs survived to the time of analysis, for a median follow-up period of 450 days (range, 204 to 1,400 days). No difference in median PFT or OST was identified between the 2 groups. CONCLUSIONS AND CLINICAL RELEVANCE Maintenance MC chemotherapy following limb amputation and completed carboplatin chemotherapy was associated with no increase in PFT or OST in dogs with appendicular osteosarcoma. Cystitis was common in MC-treated dogs, and prophylactic treatment such as furosemide administration could be considered to reduce the incidence of cystitis in such dogs.