Membrane-mediated excessive intracellular calcium accumulation (EICA) is a fundamental pathogenetic event associated with chronic muscle degeneration in patients with Duchenne muscular dystrophy (DMD), and in animals with hereditary muscular dystrophy (HMD). Because of potential Ca(2+)-channel blocking properties, we investigated the relative efficacies of chronic diltiazem (DTZM) (50 mg/kg/d), nifedipine (NFDN) (6 mg/kg/d), and verapamil (VPML) (25 mg/kg/d) therapies in reducing EICA and improving dystrophic pathobiology beginning in 30-day-old male BIO-14.6 strain dystrophic hamsters (DH). Each agent, and sterile distilled water as vehicle control, was given in a single daily oral dose for 180 days to four groups each of DH and BIO-F1B strain normal hamsters (NH). Plasma [Ca] and [Mg]; plasma aldolase (ALD), creatine kinase (CK), and lactate dehydrogenase (LDH) activities; relative cardiac hypertrophy and relative soleus hypertrophy; tissue [Ca] and [Mg] of the heart and rectus femoris muscle, histology of rectus femoris, and overall mortality rate were quantitated. Muscle Mg was not modified in DH, or by any of these agents. NFDN produced significant edema in the soleus and myocardium. During the 6-month therapeutic trial, 45% DH and 18% NH died on VPML, 27% DH and 9% NH on NFDN, and 20% DH controls on distilled water, but none on DTZM; suggesting that DTZM treated DH lived longer than DH controls. Relative efficacy in regulating EICA in both the cardiac and skeletal muscles; plasma ALD, CK, and LDH; and improving associated dystrophic pathobiology was found to be DTZM >>> NFDN > VPML. DTZM appears to be the most effective and safest agent in mitigating EICA in cardiac and skeletal muscles, efflux of intracellular enzymes, histopathology of dystrophic muscle with sporadic necrosis, and chronic muscle degeneration in DH with HMD. DTZM therapy also halted the high morbidity and mortality associated with the dystrophic pathobiology inherent in DH.