The role of partial AZFc deletions of the Y chromosome in spermatogenic impairment is currently debated. Recently, it was also reported that duplications of the same region are associated with oligozoospermia in Han-Chinese men. The aims of this study were (1) to evaluate the clinical significance of partial AZFc deletions in a large study population and (2) to define if partial AZFc duplications are a risk factor for spermatogenic failure also in a Caucasian population such as the Italian. We screened 556 infertile patients and 487 normozoospermic controls for partial AZFc deletions with a combined method based on STS+/− followed by CDY1-DAZ gene dosage and copy analysis. For the second aim, we performed CDY1-DAZ gene dosage in 229 infertile patients and 263 normozoospermic controls. The frequency of gr/gr deletions in patients was significantly different from the controls (3.2 vs. 0.4%, respectively; P < 0.001), with an OR = 7.9 (95% CI 1.8–33.8). b2/b3 deletions were rare in both groups (0.5% in patients, 0.2% in controls). Concerning gr/gr duplications, we observed no significant differences in their frequency between cases (2.6%) and controls (3.8%). This is the largest study population in the literature in which all potential methodological and selection biases were carefully avoided to detect the clinical significance of partial AZFc deletions and duplications. Our study provides strong evidence that gr/gr deletion is a risk factor for impaired spermatogenesis, whereas we did not detect a significant effect of b2/b3 deletions and partial AZFc duplications on spermatogenesis in this Caucasian ethnic group.