Background.  The objectives of this study were to estimate the incidence and evaluate risk factors for development of minocycline-induced cutaneous hyperpigmentation in patients with orthopedic infections. Methods.  Patients with orthopedic infections evaluated at Mayo Clinic (Rochester, MN) and treated with minocycline from 1 January 2002 to 31 December 2011 were retrospectively identified. Long-term minocycline suppression was defined as daily minocycline use for at least 3 months. A proportional hazards model was used to evaluate potential risk factors. Results.  Of 291 patients receiving long-term minocycline suppression, 54% (156 of 291) developed hyperpigmentation after a mean follow-up of 4.8 years (range, 0.3-13.2 years); 88% involved blue-gray pigmentation of normal skin that appeared most commonly in the lower (75%) and upper extremities (44%). The mean duration of minocycline therapy before hyperpigmentation was 1.5 years (range, 0.1-9 years) with a mean cumulative dosage of 107.3 g (range, 8.6-657 g). Notable risk factors include a history of vitamin D deficiency (relative risk [RR], 6.29; 95% confidence interval [CI], 1.91-15.27; P = .0052), presence of a shoulder prosthesis (RR, 3.2; 95% CI, 1.23-6.56; P = .0062), noncirrhotic liver pathology (RR, 3.63; 95% CI, 1.11-8.75; P = .0359), and use of a concurrent medication also known to cause hyperpigmentation (RR, 4.75; 95% CI, 1.83-10.1; P = .0029). Conclusions.  Hyperpigmentation associated with the use of long-term minocycline suppression in patients with orthopedic infections is common.