In the first of this two-part article, we reviewed essential gastrointestinal (GI) data necessary for choosing selective COX-2 inhibitors (coxibs) versus nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other NSAID-related GI issues. Although GI considerations are critical to appropriate NSAID selection, the worldwide withdrawal of rofecoxib because of adverse cardiovascular (CV) events has changed the focus of appropriate NSAID selection. In part 2, we discuss relevant CV adverse effects related to NSAID use. Based upon data reviewed, we believe there are differences between coxibs and that all NSAIDs, including nonselective agents, have some degree of CV risk. Their use should be based upon patient's risks and benefits. Our clinical use pathway or algorithm will continue to frame the ongoing discussion and guide clinicians along what has become a difficult decision in daily practice.