Objective: To review the 3 anti-inflammatory drugs, canakinumab, colchicine, and methotrexate, that have been investigated in major clinical trials for treating patients with atherosclerotic cardiovascular disease (ASCVD). Data Sources: An Ovid MEDLINE literature search (1946 to February 2, 2020) was performed using search strategy [(C-reactive protein OR ASCVD OR cardiac disease OR cardiovascular disease) AND (canakinumab OR methotrexate OR Colchicine)]. Additional references were identified from the citations. Study Selection and Data Extraction: English-language studies assessing the impact of these 3 drugs on inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) or the association with reducing ASCVD events were included. Data Synthesis: Canakinumab and colchicine significantly reduced ASCVD events in high-risk patients with median baseline hs-CRP levels of ~4.0 mg/L. Methotrexate was ineffective at reducing ASCVD events in high-risk patients, but their baseline hs-CRP concentrations were a median of <2 mg/L. In subgroup analyses of the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), patients whose baseline hs-CRP was 2 to 4 mg/L had benefits from canakinumab therapy similar to those with baseline levels exceeding 4. Relevance to Patient Care and Clinical Practice: Even with the best current drug therapies, patients with underlying inflammation can benefit from the addition of both colchicine and canakinumab to further lower CV events. Given its cost, colchicine is a more attractive option. Conclusions: Patients at high risk of recurrent cardiovascular disease events with an hs-CRP of 2 mg/L or greater can reduce the occurrence of ASCVD events with canakinumab or colchicine therapy. Colchicine is the preferable option, in particular for those with myocardial infarction, given its more reasonable cost.