This study evaluated direct relationships and associations among clinical pharmacy services, pharmacist staffing, and total cost of care in United States hospitals. A database was constructed from the 1992 American Hospital Association's Abridged Guide to the Health Care Field and the 1992 National Clinical Pharmacy Services Database. A multiple regression analysis, controlling for severity of illness, was employed to determine the relationships and associations. The study population consisted of 1016 hospitals. Six clinical pharmacy services were associated with lower total cost of care: drug use evaluation (p=0.001), drug information (p=0.003), adverse drug reaction monitoring (p=0.008), drug protocol management (p=0.001), medical rounds participation (p=0.0001), and admission drug histories (p=0.017). Two services were associated with higher total cost of care: total parenteral nutrition (TPN) team participation (p=0.001) and clinical research (p=0.0001). Total costs of care/hospital/year were lower when any of six clinical pharmacy services were present: drug use evaluation $1,119,810.18 (total $1,005,589,541.64 for the 898 hospitals offering the service), drug information $5,226,128.22 (total $1,212,461,747.04 for the 232 hospitals offering the service), adverse drug reporting monitoring $1,610,841.02 (total $1,101,815, 257.68 for the 684 hospitals offering the service), drug protocol management $1,729,608.41 (total $614,010,985.55 for the 355 hospitals offering the service), medical rounds participation $7,979,720.45 (total $1,212,917,508.41 for the 152 hospitals offering the service), and admission drug histories $6,964,145.17 (total $208,924,355.10 for the 30 hospitals offering the service). Clinical research $9,558,788.01 (total $1,013,231,529.06 for the 106 hospitals offering the service) and TPN team participation $3,211,355.12 (total $1,027,633,638.43 for the 320 hospitals offering the service) were associated with higher total costs of care. As staffing increased for hospital pharmacy administrators (p=0.0001) and clinical pharmacists (p=0.007), total cost of care decreased. As staffing increased for dispensing pharmacists, total cost of care increased (p=0.006). Based on this total cost of care model, optimal hospital pharmacy administrator staffing was 2.01/100 occupied beds. Staffing for dispensing pharmacists should be as low as possible, and definitely fewer than 5.11/100 occupied beds. Staffing for clinical pharmacists should be as high as possible, but definitely more than 1.11/100 occupied beds. The results of this study suggest that increased staffing levels of clinical pharmacists and pharmacy administrators, as well as some clinical pharmacy services, were associated with reduced total cost of care in United States hospitals.