Background: Due to the recent introduction of new biologic drugs for chronic migraine, a global evaluation in real clinical practice is necessary. Objective: The objective was to evaluate the effectiveness and safety in real clinical practice of drugs targeting the calcitonin gene-related peptide receptor (CGRPr) in patients with chronic migraine. Methods: Single-center, restrospective study (2019-2022), including patients with chronic migraine treated with erenumab, galcanezumab, or fremanezumab. Effectiveness variables were recorded, namely, number of migraine headache days per month (MHD), Migraine Disability Assessment Scale (MIDAS) score, and Headache Impact Test–6 (HIT-6) score, assessing changes at week 12, 24 from baseline. Toxicity was recorded following the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. Results: In all, 104 patients were included (46.2% erenumab, 41.3% galcanezumab, 12.5% fremanezumab). A reduction in MHD, MIDAS, and HIT-6 was achieved at weeks 12 and 24 with erenumab (p75% at week 24 than those intensified; P = 0.041). There was no difference in efficacy ( P = 0.154) or improvement in quality of life ( P = 0.783, P = 0.150), but there was greater toxicity ( P < 0.001) among nonresponders with erenumab 70 mg versus erenumab 140 mg. Conclusions: The results confirm the effectiveness and safety of anticalcitonin gene-related peptide (CGRP) drugs in real clinical practice. However, the study shows little benefit from erenumab intensification, with similar effectiveness and worse tolerability than the standard dose.