The introduction of antitumor necrosis factor (TNF) agents has improved the outcome for many patients with rheumatoid arthritis (RA). To date, the only replicated genetic predictor of anti-TNF response is the -308 G > A single-nucleotide polymorphism in the TNF promoter region. The presence of the -308 TNF G/G genotype appears to be a marker of good response to anti-TNF treatment. Anti-citrullinated protein antibodies (ACPA) have been linked with erosive disease, and have been established as the single most reliable prognostic factor in clinical practice. To test the hypothesis that the ACPA status may affect the -308 G/G patients rate of response to TNF blockade, we prospectively investigated a group of 52 RA patients with the -308 G/G genotype who were ACPA (+) or ACPA (-). All patients were treated with adalimumab, and the clinical response was studied using the Disease Activity Score in 28 joints (DAS28) at 24 weeks of treatment. Over 85% of patients were DAS28 responders in both groups. No significant differences were found between patients from both groups, according to the DAS28 criteria of response at week 24 (p = 0.79). In conclusion, our findings suggest that the ACPA status does not affect the clinical response to anti-TNF therapy in -308 TNF G/G patients.