This study examined the effect of caffeine supplementation on the white cell count and muscle damage marker responses to intermittent-interval exercise as performed by soccer players. Subjects (n = 20) completed a placebo-controlled double-blind test protocol. Forty-five minutes before exercise, participants ingested 4.5 mg·kg⁻¹ body mass of caffeine (EXP) or placebo (CONT). Blood samples were collected before and after exercise to measure hematological parameters, serum creatine kinase (CK), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP) and γ-glutamyl transferase (γ-GT) activity. To compare differences among all variables, 2 (time) × 2 (group) repeated measures ANOVA (with Tukey's post hoc tests) was conducted. Exercise caused leukocytosis (38.5% and 36.1%in EXP and CONT, respectively), lymphocytosis (42.1%and 44.9%; p < 0.05) and neutrophilia (38.2% and 31.5%; p < 0.05) without an additional effect due to caffeine (p > 0.05). Also, serum CK and LDH activity were enhanced by exercise in both groups (p < 0.05), without a synergistic effect of caffeine. ALT, AST, AP and γ-GT serum activity was not modulated by exercise or caffeine. The findings demonstrate that white cells and muscle damage markers increase after intense intermittent exercise, but acute caffeine supplementation has no influence on immune responses or muscle cellular integrity.