In 2006, Ghana ranked second in Guinea worm disease (GWD) incidence and reported a previously undocumented 20% prevalence of worm breakage. A prospective study was conducted in 2007 to validate and describe worm breakage and determinants. Among 221 patients with known outcomes, the worm breakage rate observed was 46%. After controlling for demographics, worm and wound presentation, and treatment course and provision, worm breakage was associated with narrow-diameter worms (< 2 mm) (adjusted odds ratio [AOR] 2.79; 95% confidence interval [CI] = 1.03-7.53). Protective factors against worm breakage included antibiotic ointment use (AOR 0.31; 95% CI = 0.14-0.70), bandage protocol compliance (AOR: 0.38; 95% CI = 0.16-0.89), intact bandages (AOR 0.27; 95% CI = 0.09-0.82), and bloody compared with dry wounds (AOR 0.09; 95% CI = 0.01-0.7). The high worm breakage rate observed warrants improvement in case management and patient care. Adherence to established treatment protocols should be facilitated through improved provider training and supervision to reduce the disabling consequences of broken worms.