Acne vulgaris is a skin disorder with a complex pathogenesis. Better treatment strategies require comprehensive knowledge of molecular factors contributing to the acne pathophysiology. Recent studies are focused on investigating the influence of inflammatory cytokines on the disease. This case-control study investigated the association of IL-6-572 G/C and IL-1A-889 C/T gene polymorphisms with acne in a Pakistani population. Pakistani subjects (380 healthy controls and 430 acne patients) were enrolled in this study. Polymorphism in the promoter region of IL-6-572 and IL-1A-889 was determined by polymerase chain reaction and restriction fragment length polymorphism. The IL-6-572 and IL-1A-889 variant genotypes were significantly associated with the acne pathogenesis. The IL-6-572C and the IL-1A-889T alleles were significantly high in the patient vs. control group (p < 0.0001 for both loci). The IL-6-572 G/C and IL-1A-889 C/T variant allele haplotypes showed significantly high prevalence in patients with acne; G-T (P = 0.0014), C-C (P < 0.0001), and C-T (P < 0.0001). This is the first report on the association between the IL-6-572 G/C polymorphism and acne among any population. The IL-1A-889 C/T polymorphism is also significantly linked with acne in the study population; the -889 C/T association with acne has been reported in one ethnic group previously. Our findings suggest that the IL-6-572C and IL-1A-889T alleles may contribute to the pathogenesis of acne in a Pakistani population. Further studies are required to verify these findings in other populations.