The cause of Charcot neuro-osteoarthropathy (CN) is diabetes in approximately 75% of patients. Most reports on the clinical course and complications of CN focus on diabetic CN, and reports on nondiabetic CN are scarce. No study, to our knowledge, has compared the clinical course of patients initially treated nonoperatively for diabetic and nondiabetic CN. Among patients with CN, are there differences between patients with diabetes and those without in terms of (1) the frequency of major amputation as ascertained by a competing risks survivorship estimator; (2) the frequency of surgery as ascertained by a competing risks survivorship estimator; (3) frequency of reactivation, as above; or (4) other complications (contralateral CN development or ulcers)? Between January 1, 2006, and December 31, 2018, we treated 199 patients for diabetic CN. Eleven percent (22 of 199) were lost before the minimum study follow-up of 2 years or had incomplete datasets and could not be analyzed, and another 9% (18 of 199) were excluded for other prespecified reasons, leaving 80% (159 of 199) for analysis in this retrospective study at a mean follow-up duration since diagnosis of 6 ± 4 years. During that period, we also treated 78 patients for nondiabetic Charcot arthropathy. Eighteen percent (14 of 78) were lost before the minimum study follow-up and another 5% (four of 78 patients) were excluded for other prespecified reasons, leaving 77% (60 of 78) of patients for analysis here at a mean of 5 ± 3 years. Patients with diabetic CN were younger (59 ± 11 years versus 68 ± 11 years; p < 0.01), more likely to smoke cigarettes (37% [59 of 159] versus 20% [12 of 60]; p = 0.02), and had longer follow-up (6 ± 4 years versus 5 ± 3 years; p = 0.02) than those with nondiabetic CN. Gender, BMI, overall renal failure, dialysis, and presence of peripheral arterial disease did not differ between the groups. Age difference and length of follow-up were not considered disqualifying problems because of the later onset of idiopathic neuropathy and longer available patient follow-up in patients with diabetes, because our program adheres to the follow-up recommendations suggested by the International Working Group on the Diabetic Foot. Treatment was the same in both groups and included serial total-contact casting and restricted weightbearing until CN had resolved. Then, patients subsequently transitioned to orthopaedic footwear. CN reactivation was defined as clinical signs of the recurrence of CN activity and confirmation on MRI. Group-specific risks of the frequencies of major amputation, surgery, and CN reactivation were calculated, accounting for competing events. Group comparisons and confounder analyses were conducted on these data with a Cox regression analysis. Other complications (contralateral CN development and ulcers) are described descriptively to avoid pooling of complications with varying severity, which could be misleading. The risk of major amputation (defined as an above-ankle amputation), estimated using a competing risks survivorship estimator, was not different between the diabetic CN group and nondiabetic CN group at 10 years (8.8% [95% confidence interval 4.2% to 15%] versus 6.9% [95% CI 0.9% to 22%]; p = 0.4) after controlling for potentially confounding variables such as smoking and peripheral artery disease. The risk of any surgery was no different between the groups as estimated by the survivorship function at 10 years (53% [95% CI 42% to 63%] versus 58% [95% CI 23% to 82%]; p = 0.3), with smoking (hazard ratio 2.4 [95% CI 1.6 to 3.6]) and peripheral artery disease (HR 2.2 [95% CI 1.4 to 3.4]) being associated with diabetic CN. Likewise, there was no between-group difference in CN reactivation at 10 years (16% [95% CI 9% to 23%] versus 11% [95% CI 4.5% to 22%]; p = 0.7) after controlling for potentially confounding variables such as smoking and peripheral artery disease. Contralateral CN occurred in 17% (27 of 159) of patients in the diabetic group and in 10% (six of 60) of those in the nondiabetic group. Ulcers occurred in 74% (117 of 159) of patients in the diabetic group and in 65% (39 of 60) of those in the nondiabetic group. Irrespective of whether the etiology of CN is diabetic or nondiabetic, our results suggest that orthopaedic surgeons should use similar nonsurgical treatments, with total-contact casting until CN activity has resolved, and then proceed with orthopaedic footwear. A high frequency of foot ulcers must be anticipated and addressed as part of the treatment approach. Level III, prognostic study.