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<i>Fuzzless-lintless</i> mutant (<i>fl</i>) ovules of upland cotton have been used to investigate cotton fiber development for decades. However, the molecular differences of green tissues between <i>fl</i> and wild-type (WT) cotton were barely reported. Here, we found that gossypol content, the most important secondary metabolite of cotton leaves, was higher in <i>Gossypium hirsutum</i> L. cv Xuzhou-142 (Xu142) WT than in <i>fl</i>. Then, we performed comparative proteomic analysis of the leaves from Xu142 WT and its <i>fl</i>. A total of 4506 proteins were identified, of which 103 and 164 appeared to be WT- and <i>fl</i>-specific, respectively. In the 4239 common-expressed proteins, 80 and 74 were preferentially accumulated in WT and <i>fl</i>, respectively. Pathway enrichment analysis and protein&#8722;protein interaction network analysis of both variety-specific and differential abundant proteins showed that secondary metabolism and chloroplast-related pathways were significantly enriched. Quantitative real-time PCR confirmed that the expression levels of 12 out of 16 selected genes from representative pathways were consistent with their protein accumulation patterns. Further analyses showed that the content of chlorophyll a in WT, but not chlorophyll b, was significantly increased compared to <i>fl</i>. This work provides the leaf proteome profiles of Xu142 and its <i>fl</i> mutant, indicating the necessity of further investigation of molecular differences between WT and <i>fl</i> leaves.