Objective: Calcium pyrophosphate deposition disease (CPDD) is a common cause of acute and chronic arthritis, yet there are few large epidemiologic studies of CPDD. We sought to characterize CPDD in the national Veterans Affairs (VA) population. Methods: Using data from the Department of VA Corporate Data Warehouse, patients with International Classification of Diseases, Ninth Revision, codes for CPDD seen at any VA medical center from 2010 through 2014 were matched by age and sex with control patients without CPDD. We used multivariate analysis to compare the prevalence and odds ratios (ORs) of various comorbidities, substance use, medication exposures, and arthroplasties among patients with and without CPDD. Results: We identified 25,157 patients with CPDD, yielding a point prevalence of 5.2 per 1,000. The mean ± SD age was 68.1 ± 12.3 years, and 95% were male. The strongest positive associations with CPDD were hyperparathyroidism (OR 3.35 [95% confidence interval (95% CI) 2.96–3.79]), gout (OR 2.82 [95% CI 2.69–2.95]), osteoarthritis (OR 2.26 [95% CI 2.15–2.37]), rheumatoid arthritis (OR 1.88 [95% CI 1.74–2.03]), and hemochromatosis (OR 1.87 [95% CI 1.57–2.24]). Positive associations were also seen with higher odds for osteoporosis (OR 1.26 [95% CI 1.16–1.36]), hypomagnesemia (OR 1.23 [95% CI 1.16–1.30]), chronic kidney disease (OR 1.12 [95% CI 1.07–1.18]), and calcium supplementation (OR 1.15 [95% CI 1.06–1.24). Negative associations were seen with proton-pump inhibitors (OR 0.58 [95% CI 0.55–0.60]) and loop diuretics (OR 0.80 [95% CI 0.76–0.84]). Conclusion: Using a large national data set, we confirmed known associations with CPDD, provided support for positive associations with rheumatoid arthritis, hypomagnesemia, and osteoporosis, and suggested potential novel negative associations with commonly used medications.