Creatine has been reported to be an effective ergogenic aid for athletes. However, concerns have been raised regarding the long-term safety of creatine supplementation. This study examined the effects of long-term creatine supplementation on a 69-item panel of serum, whole blood, and urinary markers of clinical health status in athletes. Over a 21-month period, 98 Division IA college football players were administered in an open label manner creatine or non-creatine containing supplements following training sessions. Subjects who ingested creatine were administered 15.75 g/day of creatine monohydrate for 5 days and an average of 5 g/day thereafter in 5-10 g/day doses. Fasting blood and 24-h urine samples were collected at 0, 1, 1.5, 4, 6, 10, 12, 17, and 21 months of training. A comprehensive quantitative clinical chemistry panel was determined on serum and whole blood samples (metabolic markers, muscle and liver enzymes, electrolytes, lipid profiles, hematological markers, and lymphocytes). In addition, urine samples were quantitatively and qualitative analyzed to assess clinical status and renal function. At the end of the study, subjects were categorized into groups that did not take creatine (n = 44) and subjects who took creatine for 0-6 months (mean 4.4 +/- 1.8 months, n = 12), 7-12 months (mean 9.3 +/- 2.0 months, n = 25), and 12-21 months (mean 19.3 +/- 2.4 months, n = 17). Baseline and the subjects' final blood and urine samples were analyzed by MANOVA and 2 x 2 repeated measures ANOVA univariate tests. MANOVA revealed no significant differences (p = 0.51) among groups in the 54-item panel of quantitative blood and urine markers assessed. Univariate analysis revealed no clinically significant interactions among groups in markers of clinical status. In addition, no apparent differences were observed among groups in the 15-item panel of qualitative urine markers. Results indicate that long-term creatine supplementation (up to 21-months) does not appear to adversely effect markers of health status in athletes undergoing intense training in comparison to athletes who do not take creatine.